PET ligands and metabolic brain imaging Prof. Karl Herholz

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1 PET ligands Karl Herholz, University of Manchester PET images in this lecture, unless indicated otherwise, are from Max-Planck-Institute for Neurological Research, Cologne, Germany 1 Positron-Emission-Tomography (PET) Short-lived 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 2 Positron Emission Tomography (PET) F-18 (110 min) C-11 (20 min) I-124 (4 d) O-15 (2 min) The screen versions of these slides have full details of copyright and acknowledgements 1

2 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 4 Imaging of Local Brain Function Neuronal function Ion gradients Transmitter synthesis and recycling Energy consumption: FDG-PET Blood flow: PET, SPECT, fmri 5 FDG-PET: Normal cerebral glucose metabolism 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 fuctional impairment of CMRGlc in association cortex First symptoms: "Mild cognitive impairment" FDG-PET: Progression of early-onset Alzheimer Disease progression of CMRGlc reduction in association cortex 14 months later increase of extent and severity of CMRGlc reduction mild dementia 7 Posterior cingulate impairment in Alzheimer s disease 8 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 9 The screen versions of these slides have full details of copyright and acknowledgements 3

4 Comparison of CMRGlc Reduction due to Age (n=110) and AD (n=394) Herholz et al., Neuroimage, 2002 grey matter mask age (normals) MMSE (AD) age & MMSE 10 Diagnostic Accuracy of FDG PET for detection of Alzheimer's Disease Comparison N=395 (AD), N=110 (C) Sensitivity Specificity All probable AD vs. controls 93% 93% Very mild AD (MMSE >= 24) vs. controls 84% 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: (2002) 11 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 Technologies Inc. 12 The screen versions of these slides have full details of copyright and acknowledgements 4

5 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, however 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 13 Progressive prosopagnosia In most cases (Tung-Wai et al, Neurolog y, 2004) posterior variant of Alzheimer s disease 14 Frontal brain areas show reduced glucose metabolism in depression Holthoff et al., Acta Psychiatr.Scand. 110: (2004) Holthoff et al., Biol.Psychiatry 57(4): (2005) 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Anosognosia in AD: Metabolic changes related to patients' self assessment E. Salmon et al., Human Brain Mapping, In press 16 Metabolic impairment in FDG PET predicts clinical deterioration in mild cognitive impairment ("possible Alzheimer's disease") n FDG PET abnormality at entry Frequency (%) of deterioration within 2 years EC Multicenter Study: 52 patients with MMSE >= Herholz K et al. Dementia & Geriatric Cognitive Disorders 1999; 10(6): Prospective study of FDG PET in MCI (Anchisi et al., Arch Neurol, in press) Within 1 year: dementia no progression Positive predictive value Negative predictive value CVLT 48% 93% PET 93% 93% Reduction of temporoparietal FDG uptake Memory performance (CVLT) 18 The screen versions of these slides have full details of copyright and acknowledgements 6

7 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) 19 Frontotemporal Dementia asymmetric frontotemporal atrophy and functional impairment FDG PET 20 Impairment of Ventromedial Frontopol ar Cortex in Fronto-temporal Dementia Salmon E, et al Neuroimag e 20, The screen versions of these slides have full details of copyright and acknowledgements 7

8 Proposed functions of 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) 22 Fronto-Temporal Dementia with Amyotrophic Lateral Sclerosis FDG PET: CMRGlc MPI Cologne 23 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 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 Corticobasal Degeneration Mild reduction of CMRglc and FDOPA uptake in left striatum Severe atrophy and metaboli c impairment of left parietal cortex 25 Progressive supranuclear palsy Mild gait disorder, no definitive clinical diagnosis 7 years later: supranuclear palsy, severe falls, parkinsonism CMRGlc deviation from normal 26 Chorea Huntington Atrophy and functional lesion of basal ganglia Normal control 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 FDG PET Metabolic Signatures Disease Brain regions with reduced FDG uptake Alzheimer disease (AD) Dementia with Lewy bodies (LBD) Frontotemporal dementia (FTD) Parkinson disease (PD) Olivo-ponto -cerebellar atrophy Striato-nigral degeneration Progressive supranuclear palsy Corticobasal degeneration Spinocerebellar degeneration Chorea Huntington temporoparietal association cortex, posterior cingulate cortex and precuneus, variably also frontolateral association cortex as in AD, plus primary visual cortex (FDOPA is abnormal, in contrast to AD) predominantly frontomesial, also frontolateral and anterior part of temporal lobe FDG PET usually normal (apart from atrophy effects), but cortical impairment similar to LBD is possible in late stages of the disease putamen, brainstem, cerebellum, often also cerebral cortex putamen frontal, basal ganglia and midbrain mainly parietal, central and frontal cortex, striatum and thalamus, often very asymmetric (contralateral to side of clinical symptoms) variable, probably depending on subtype, may be similar to OPCA caudate nuclei, putamen, with progression also thalamus and cortex 28 Imaging cerebral amyloid Pittsburg Compound-B (PIB) {N-methyl-[11C]}2-(4 -methylaminophenyl)-6-hydroxybenzothiazole Klunk et al. (2005) In: Herholz, Perani & Morris: The dementias (Dekker) 29 Tracers for the Dopaminergic System Presynaptic: Dopaminergic Axon Dopamin-Synthesis: 18 F-fluorodopa Postsynaptic: Striatal Neuron D2-Receptors: 11 C-raclopride, 18 F-fallypride 123 I-IBZM Vesicle transporter (VMAT2) 11 C-dihydrotetrabenazine Reuptake Receptors: 18 F-CFT, 11 C-PE2I 123I-βCIT, 99m Tc-TRODAT 30 The screen versions of these slides have full details of copyright and acknowledgements 10

11 Anatomy of the Dopaminergic System F-DOPA PET-MRI Fusion 31 Mild Parkinson s disease (HY2) CMRglc intact in striatum and cortex FDG 4 years later CMRglc intact in striatum but reduced in cortex Dopamine synthesis impaired in striatum, most severely in right caudal putamen FDOPA Progression of impairment of dopamine synthesis D2 receptors upregulated in right caudal putamen but slightly reduced in caudate RAC D2 receptors similar to first study 32 Progression of Parkinson s disease log FDOPA Ki Putamen x - 1,9 normal controls (n = 16) - c - 2,0 baseline PET scan follow-up PET scan K i (t 0 ) - 2,1 K i (t 1 ) - 2,2 K i (t 2 ) - 2,3-2,4 preclincial period - 2,5 t pre t 1 t disease duration (years) Hilker et al., Arch Neurol., The screen versions of these slides have full details of copyright and acknowledgements 11

12 Striatonigral degeneration (SD) compared to Parkinson's disease (PD) FDG FDOPA Raclopride 34 Pre- and postsynaptic Changes 35 brain: basal forebrain pedunculopontine tegmental neurons striatal interneurons cranial nerve nuclei vestibular nuclei Cholinergic systems spinal cord: preganglionic neurons motor neurons E. Perry, The screen versions of these slides have full details of copyright and acknowledgements 12

13 PET- Tracers for the cholinergic system Acetylcholine esterase (AChE) C-11-N-methyl-4-piperidyl-acetate (MP4A) C-11-N-methyl-4-piperidyl-propionate (MP4P) Muscarinic receptors C-11-N-methyl-4-piperidylbenzilate (NMPB) Nicotinic receptors F-18-fluoro-A C-11-nicotine 37 MP4A ACh C-11-MP4A (C-11-methyl-4- piperidyl- acet at e) Kinetic Model (Namba et al., 1994) Blood Brain CH 3 -N O -O-C-CH 3 hydrolysis K 1 O CH 3 -N -O-C-CH 3 k 2 k 3 (hydrolysis) CH 3 -N -OH CH 3 -N -OH metabolic trap MPI/Uni Cologne 39 The screen versions of these slides have full details of copyright and acknowledgements 13

14 AChE activity measured by C-11-MP4A k 3 Parametric images of hydrolysis rates 40 C-11-MP4A PET in mild to moderate AD: C Preservation of AChE in Nucleus basalis Meynert (Herholz et al., Neuroimage,2004) AD reduced neocortical and amygdaloid AChE activity normal AChE activity in nbm region 41 Cortical AChE activity in MCI is associated with progress to dementia 0.14 Converted to AD [month of detected conversion] [6] [14] [18] [18] 0.14 No conversion to AD within 18 months Herholz et al., Neuroreport, The screen versions of these slides have full details of copyright and acknowledgements 14

15 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 typically well formed and detailed Spontaneous motor features of parkinsonism McKeith et al., 1996 Impairment of temporal and occipital glucose metabolism 43 Transmitter Deficits in Lewy Body Dementia: MP4A: Reduction of cortical AChE activity F-DOPA: Dopaminergic deficit in striatum 44 Cholinergic but not dopaminergic deficit differentiates between Parkinson s disease (IPS) and Dementia with Lewy bodies (LBD),11,016,10,09,014,08,012,07,010 Mean cerebral AChE activity,06,05,04,03,02,01 0,00 Cont rol IPS LBD Dopa influx Putamen,008,006,004,002 0,000 Control Dopa IPS LBD AChE activity Dopamine synthesis 45 The screen versions of these slides have full details of copyright and acknowledgements 15

16 Systems Impairment in Degenerative Dementia Dementia Type Alzheimer dementia Dementia with Lewy bodies Frontotemporal dementia Function: FDG Posterior cingulate/precuneus, angular gyrus similar to AD, plus visual cortex Frontomesial, with variable extension to frontolateral and anterior temporal cortex Subsystem impairment Cholinergic: MP4A cortical severe cortical intact Dopaminergic: FDOPA intact impaired intact 46 FDG Clinical PET Tracers for Neurodegenerative Diseases 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) The screen versions of these slides have full details of copyright and acknowledgements 16