pet ligands and metabolic brain imaging prof. karl herholz · progressive prosopagnosia in most...
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PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 1
1
Karl Herholz, University of Manchester
PET ligands
and metabolic brain imaging
PET images in this lecture, unless indicated otherwise, are from
Max-Planck-Ins titute for Neurological Research, Cologne, Germany
2
Positron-Emission-Tomography (PET)
Short-l ived positron emitting isotopes produced by cyclotron
Isotopes coupled to minute (typically microgram) amounts of biomolecules ► tracer
Tracer injected intravenously into patient
Coincidence events caused by pairs of 511keV γ-rays (originating from electron-positron annihilation) detected by PET camera
Local metabolic rates and binding potentials calculated from kinetics of in-vivo tracer biodistribution
Positron Emission Tomography (PET)
F-18 (110 min) C-11 (20 min)
O-15 (2 min)I-124 (4 d)
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 2
4
Frequent neurodegenerative diseases
with characteristic PET findings
Alzheimer's disease
Frontotemporal dementia
(Pick complex)
Dementia
with Lewy bodies
Parkinson’s disease
Multiple system atrophy
Huntington’s disease
Amyotrophic
lateral sclerosis
PET findings
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Ion gradients
Transmitter synthesis and recycling
Imaging of Local Brain Function
Neuronal function
Energy consumption:FDG-PET
Blood flow:PET, SPECT, fMRI
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FDG-PET:Normal cerebral glucose metabolism
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 3
7
FDG-PET:
Progression
of early-on set
Alzheimer
Disease
First symptoms:"Mild cognitive
impairment"
14 months later
mild dementia
progression of CMRGlc reduction in association cortex
increase of extent and severity of CMRGlc reduction
fuctional impairment of CMRGlc in association cortex
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
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Posterior cingulate impairment in Alzheimer’s disease
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Posterior Cingulate and Precuneus
in Normal Subjects
Function (seen in activation studies):
Episodic memory, esp. Retrieval
"The mind's eye": Imagery in episodic recall
Integrating current input with background knowledge
Autobiographical memory retrieval
Resting glucose metabolic activity
related to education
slightly reduced in ApoE4 carriers
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 4
10grey matter mask MMSE (AD)age (normals) age & MMSE
Comparison of CMRGlc Reduction due to Age (n=110) and AD (n=394)
He
rho
lz et al., N
eu
roim
ag
e, 2002
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Diagnostic Accuracy of FDG PET for detection of Alzheimer's Disease
ComparisonN=395 (AD), N=110 (C) Sensitivity Specificity
All probable AD vs. controls 93% 93%
Very mild AD (MMSE >= 24)
vs. controls84% 93%
Earliest AD vs. controls
(matched by MMSE 27-29) 83% 82%
Herholz K, et al.: Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET. Neuroimage 17: 302-316 (2002)
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Automatic detection of abnormal metabolism
and regions that are typically affected by AD
T-statistics compared to European network (NEST-DD) normal database
with correction for scanner resolution and patient age
Herholz et al.Neuroimage
2002
Software by:PMOD
TechnologiesInc.
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 5
13
Late vs. early onset AD
The selective metabolic impairment in temporo-parietal and posterior cingulate cortex is more pronounced in familial AD with early onset than in late-onset AD, which is mostly sporadic. Overall cortical impairment is similar, howeverF
Vascular dementia also shows mostly global metabolic impairment without much regional selectivity
Multifactorial etiology, which is common in late onset dementia, is related to widespread cerebral metabolic impairment
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Progressive prosopagnosia
In most cases (Tung-Wai et al, Neurolog y, 2004)
“posterior variant of Alzheimer’s disease”
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Frontal brain areas show reduced glucose metabolism in depression
Holthoff et al., Acta Psychiatr.Scand. 110: 184-194 (2004)
Holthoff et al., Biol.Psychiatry 57(4):412-421 (2005)
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 6
16
Anosognosia in AD:
Metabolic changes
related to patients'
self assessment
E. Salmon et al.,
Human Brain Mapping,
In press
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Metabolic impairment in FDG PET predicts clinical deterioration in mild cognitive impairment
("possible Alzheimer's disease")
EC Multicenter Study:52 patients with MMSE >= 24
Herholz K et al. Dementia & Geriatric Cognitive Disorders 1999; 10(6):494-504.
deterioration
Frequency(%) of
within 2 years
FDG PET abnormality at entry
0
10
20
30
40
50
60
70
+ ++ +++n
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Prospective study
of FDG PET
in MCI(Anchisi et al.,
Arch Neurol, in press)
dementia
no progression
Within 1 year:
Re
du
cti
on
of te
mp
oro
pa
rie
tal F
DG
up
take
Memory performance (CVLT)
Positive predictive
value
Negative predictive
value
CVLT 48% 93%
PET 93% 93%
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 7
19
Fronto-temporal Dementia (FTD)
Changes of personality and executive function, aphasia
Apathy or disinhibited, bizarre behavior
Fronto-temporal “lobar” atrophy
Mostly sporadic
rarely autosomal dominant (tau gene at 17q21-22)
Various inconstant histopathological changes
(astrogliosis, neuronal loss, Pick bodies, basophilic inclusion bodies,
ubiquinated tau-negati ve non-eosi nophilic inclusions)
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Frontotemporal Dementiaasymmetric frontotemporal atrophy
and functional impairment
FDG
PET
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
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Impairment of Ventromedial Frontopolar Cortex
in Fronto-temporal Dementia
Salmon E, et al. 2003. Neuroimag e 20,435-440
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 8
22
Proposed functionsof frontomesial cortex in activation studies
"Theory of mind" (Fletcher et al., 1995)
Self-referential mental activity (Maguire et al., 1999)
Self-initiated, intentional thoughts (McGuire et al., 1996)
Subjective emotional responses
(Lane et al. 1997)
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Fronto-Temporal Dementia with Amyotrophic Lateral Sclerosis
MPICologne
FDGPET:CMRGlc
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Frontotemporal Lobar Atrophies
Often with pathological protein tau deposits (“tauopathy”), similar to fronto-temporal dementia
Primary progressiv e aphasia
Nonfluent progressive aphasie
Mostly left inferior frontal and temporal metabolic impairment and atrophy
Semantic dementia
Severe progressive disturbance of semantic memory
Mostly left temporal (and frontal) metabolic impairment and atrophy
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 9
25
Mild reduction
of CMRglc and
FDOPA uptake
in left striatum
Severe atrophy
and metaboli c
impairment of left
parietal cortex
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
Corticobasal Degeneration
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Mild gait d isorder,
no definitive
clinical diagnosis
7 years later:
supranuclear palsy,
severe falls,
parkinsonism
CMRGlcdeviation
from normal
Progressive supranuclear palsy
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
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Chorea Huntington
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
Atrophy and functional
lesion of basal ganglia
Normal control
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 10
28
FDG PET Metabolic SignaturesDisease Brain regions with reduced FDG uptake
Alzheimer disease (AD)temporoparietal association cortex, posterior cingulate cortex and precuneus, variably also frontolateral association cortex
Dementia with Lewy bodies (LBD)
as in AD, plus primary visual cortex (FDOPA is abnormal, in contrast to AD)
Frontotemporal dementia (FTD)
predominantly frontomesial, also frontolateral and anterior part of temporal lobe
Parkinson disease (PD)FDG PET usually normal (apart from atrophy effects), but cortical impairment similar to LBD is possible in late stages of the disease
Olivo-ponto-cerebellar atrophy
putamen, brainstem, cerebellum, often also cerebral cortex
Striato-nigral degeneration putamen
Progressive supranuclear palsy
frontal, basal ganglia and midbrain
Corticobasal degenerationmainly parietal, central and frontal cortex, striatum and thalamus, often very asymmetric (contralateral to side of clinical symptoms)
Spinocerebellar degeneration
variable, probably depending on subtype, may be similar to OPCA
Chorea Huntingtoncaudate nuclei, putamen, with progression also thalamus and cortex
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
29Klunk et al. (2005) In: Herholz, Perani & Morris: The dementi as (Dekker)
Imaging cerebral amyloid
Pittsburg Compound-B (PIB){N-methyl-[11C]}2-(4’-methylaminophenyl)-6-hydroxybenzothiazole
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Tracers for the Dopaminergic System
Presynaptic:
Dopaminergic AxonPostsynaptic:
Striatal Neuron
Dopamin-Synthesis:18F-fluorodopa
D2-Receptors:11C-raclopride, 18F-fallypride123I-IBZM
Vesicle transporter (VMAT2)11C-dihydrotetrabenazine
Reuptake Receptors:18F-CFT, 11C-PE2I123I-βCIT, 99mTc-TRODAT
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 11
31
Anatomy of the Dopaminergic SystemF-DOPA PET-MRI Fusion
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FDG
FDOPA
RAC
Mild Parkinson‘s
disease (HY2) 4 years later
CMRglc intactin striatumand cortex
CMRglc intactin striatumbut reducedin cortex
Dopamine synthesisimpaired in striatum,most severely inright caudal putamen
Progression of impairment of dopamine synthesis
D2 receptorsupregulated in right caudal putamenbut slightly reduced
in caudate
D2 receptorssimilar to first study
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
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Progression of Parkinson’s disease
disea se durat ion (yea rs)
- 10 -5 0 5 10 15
- 2,5
- 2,4
- 2,3
- 2,2
- 2,1
- 2,0
- 1,9
base line PE T sca n
follow-up PET sc an
norma l controls (n = 16)
log FDOPA Ki Puta men
Ki (t1)
t1
prec lincial period
tpr e
- c
Ki (t0)
x
Ki (t2)
t2
Hilker et al., Arch Neurol., 2005
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 12
34
Striatonigral degeneration (SD)compared to Parkinson's disease (PD)
FDG
FDOPA
Raclopride
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Pre- and postsynaptic Changes
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
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Cholinergic systems
brain:
basal forebrain
pedunculopontine
tegmental neurons
striatal interneurons
cranial nerve nuclei
vestibular nuclei
spinal cord:
preganglionic neurons
motor neuronsE. Perry, 1999
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 13
37
PET- Tracersfor the cholinergic system
Acetylcholine esterase (AChE)C-11-N-methyl-4-piperidyl-acetate (MP4A)
C-11-N-methyl-4-piperidyl-propionate (MP4P)
Muscarinic receptorsC-11-N-methyl-4-piperidylbenzilate (NMPB)
Nicotinic receptorsF-18-fluoro-A-85380
C-11-nicotine
MP4A AChMP4A ACh
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C-11-MP4A (C-11-methyl-4- pip er id yl- acet at e)
Kinetic Model (Namba et al., 1994)
MPI/Uni Cologne
-O-C-CH3CH3-N
O
Blood Brain
K1
-O-C-CH3
O
CH3-Nk2
k3 (hydrolysis)
metabolic trap
-OHCH3-N-OHCH3-N
hydrolysis
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 14
40
AChE activity measured by C-11-MP4A
k3
Parametric images of hydrolysis rates
41
C
AD
C-11-MP4A PET
in mild
to moderate AD:
Preservation
of AChE
in Nucleus
basalis Meynert
(Herholz et al.,
Neuroimage,2004)
normal AChE activity in nbM region
reduced neocortical and amygdaloid AChE activity
42
Cortical AChE activity in MCIis associated with progress to dementia
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14 Converted to AD [month of detected conversion]
[6] [14] [18] [18]
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14 No conversion to AD within 18 months
Herholz et al., Neuroreport, 2005
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 15
43
Dementia with Lewy Bodies (DLB)
Essential symptoms (2 of 3) for clinical diagnosis
Fluctuating cognition with pronounced variations in attention and alertness
Recurrent visual hallucinati ons that are typicall y well formed and detailed
Spontaneous motor features of parkinsonism
McKeith et al., 1996
Impairment of
temporal and occipital
glucose metabolism
44
Transmitter Deficits in Lewy Body Dementia:
F-DOPA:
Dopaminergic
deficit
in striatum
MP4A:
Reduction
of cortical AChE
activity
From: Herholz et al., NeuroPET, Springer-Verlag, 2004
45
Cholinergic but not dopaminergic deficitdifferentiates between Parkinson‘s disease (IPS)
and Dementia with Lewy bodies (LBD)
LBDIPSCont rol
Mean c
ere
bra
l AC
hE
activ
ity
,11
,10
,09
,08
,07
,06
,05
,04
,03
,02
,01
0,00
LBDIPSControl Dopa
Dopa
influx P
uta
me
n
,016
,014
,012
,010
,008
,006
,004
,002
0,000
AChE activity Dopamine synthesis
PET ligands
and metabolic brain imaging
Prof. Karl Herholz
The screen versions of these slides have full details of copyright and acknowledgements 16
46
Systems Impairment inDegenerative Dementia
Dementia Type
Subsystem impairment
Function: FDG Cholinergic:MP4A
Dopaminergic:FDOPA
Alzheimer dementia
Posterior cingulate/precuneus,
angular gyruscortical intact
Dementia with Lewy bodies
similar to AD, plus visual cortex
severe cortical
impaired
Frontotemporal dementia
Frontomesial, with variable extension to
frontolateral and anterior temporal
cortex
intact intact
47
Clinical PET Tracers for Neurodegenerative Diseases
FDG
All neurodegenerative diseases: often typical regional distribution of metabolic deficits
Relevant for diagnosis of AD at the clinical stage of mild cognitive impairment (MCI)
FDOPA
Reduced uptake in dementia with Lewy bodies (in contrast to AD) and in PD
Others to study specific deficits and drug effects (mostly in the context of neuroscience research)
48