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

5

Ion gradients

Transmitter synthesis and recycling

Imaging of Local Brain Function

Neuronal function

Energy consumption:FDG-PET

Blood flow:PET, SPECT, fMRI

6

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

8

Posterior cingulate impairment in Alzheimer’s disease

9

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

11

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)

12

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

14

Progressive prosopagnosia

In most cases (Tung-Wai et al, Neurolog y, 2004)

“posterior variant of Alzheimer’s disease”

15

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

17

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

18

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)

20

Frontotemporal Dementiaasymmetric frontotemporal atrophy

and functional impairment

FDG

PET

From: Herholz et al., NeuroPET, Springer-Verlag, 2004

21

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)

23

Fronto-Temporal Dementia with Amyotrophic Lateral Sclerosis

MPICologne

FDGPET:CMRGlc

24

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

26

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

27

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

30

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

32

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

33

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

35

Pre- and postsynaptic Changes

From: Herholz et al., NeuroPET, Springer-Verlag, 2004

36

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

39

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