Conclusion slide: AMA-UCL May 12, 2007

Conclusion slide: AMA-UCL May 12, 2007 uveautés en Imagerie : le DAT scan Prof. Thierry Vander Borght Service de Médecine Nucléaire UCL Mont-Godinne The day may not be far off when molecular imaging methods are standard tools for clinical practice in neurology. Roger L Albin Geriatrics Research, Education and Clinical Center, Ann Arbor. VAMC, Ann Arbor, MI, USA; and Department of Neurology, University of Michigan, Ann Arbor, MI, USA Lancet Neurol 2007; 6:288-9. Anatomy Global Function Specific Function DA Pathways Ctscan/MRI Atrophy fmri, SPECT, PET Distribution pattern SPECT, PET Cellular dysfunction 1) Tuberoinfundibular 2) Mesolimbic reward/salience pleasure, euphoria motor function compulsion Perseveration 3) Nigrostriatal Size Earliness Dopaminergic synapse A Good Radiotracer Nigro-striatal neuron Tyrosine Tyrosine-hydroxylase L-Dopa Dopa-decarboxylase Dopamine MAO-A Glial cell metabolites ² MAO-B Design Parameters 1. Must have an appropriate target 2. High in vitro affinity and selectivity for target 3. Able to be radiolabeled routinely 4. Target accessibility 5. Low non-specific binding Post-synaptic synaptic neuron D1 Test Criteria 6. Good signal to noise ratio in vivo 7. Appropriate in vivo pharmacokinetics 8. Appropriate in vivo distribution and pharmacology 9. Low amounts of labeled metabolites in the ROI 10.Sensitivity towards target 1

Dopaminergic synapse Nigro-striatal neuron Tyrosine Tyrosine-hydroxylase [ 11 C]-tetrabenazine L-Dopa F]-FluoroDOPA FluoroDOPA Dopa-decarboxylase Dopamine [ 18 F] [ 11 C]-SCH 23390 [ 123 I]-FP FP-CIT (DaTSCAN ( ) [ 11 C]-PE2I, [ 123 I]-PE2I [ 123 I]-b-CIT D1 [ 76 Br]-FE FE-CBT [ 11 C]-CFT, CFT, [ 11 C]-RTI32 Post-synaptic synaptic neuron [ 11 C]-deprenyl [ 11 C]-befloxatone Glial cell MAO-A métabolites ² [ 11 C]-raclopride MAO-B Assessment of the presynaptic DA system with PET & SPECT [ 18 F]FDOPA PET [ 11 C]DTBZ PET [ 11 C]FE-CIT PET AADC VMAT2 DAT Prof. Bartenstein Prof. Frey Prof. Antonini Univ. Mainz Univ. of Michigan Milano [ 123 I]ß-CIT SPECT [ 123 I]FP-CIT SPECT [ 99m Tc]TRODAT-1 SPECT DAT DAT DAT 18-24 h p.i. 3-6 h p.i. 3-4 h p.i. Metabolite Analogues: FDOPA Presynaptic DA Terminal BRAIN FDA vesicle DAT OMeFDOPA FDOPA FDA FDOPAC BBB FHVA VMAT2 ATP ADP CaM Kinase II Vesicular Lumen OMeFDOPA FDOPA Extracellular Exocytosis Pase P i Recycling H 2 O H 2 N HOOC Cytoplasm Limitations CIRCULATION Expensive Metabolization t specific for DA neurons Uptake = f(dopamine turnover) NH 2 COOH Cytoplasm 1000 40 nm vesicles Proton exchange Monoamine (-) reserpine, TBZ, ketanserin 1000 DAT Cotransport of cation Dopamine (-) antidepressant, cocaine SERVICE HOSPITALIER FREDERIC JOLIOT Dopaminergic function and dopamine transporter binding in Parkinson s disease [ 18 F]-DOPA 1.6 Putamen % 100 [ 18 F]-DOPA [ 76 Br]-FE-CBT 80 60 ~20% [ 76 Br]-FE-CBT 0 2.8 40 20 Poewe & Scherfler. Mov Disoder 2003;18:S16-21. early drug-naive PD advanced PD 0 0 less more affected Early PD less more affected Advanced PD Ribeiro et al. Arch Neurol 2002 2

Radioligand I]FP-CIT [ 123 I]Altropane DAT Radioligands STR/CBL Time Max (min) DA/5HT [ 99m Tc]Trodat 2 120-140 5/1 - Brain metabolites [ 123 I]β -CIT >12 > 1200 1.7 + [ 123 4 6 90-120 2.8-30 28 - Practical aspects for clinical use: Medication-interactions for DAT imaging CNS Stimulants cocaine, crack cocaine amfetamine + analogs R/ for ADHD, epilepsy, nacrolepsy methylphenidate (Ritaline) Most anti-anorectic and anti-obesities drugs dextroamphetamine phenylpropanolamine phentermine, mazindol Sympathomimetics (nasal decongestant) norephedrine phenylpropanolamine Some antidepressants (esp. tricyclic) amoxapine, buspirone NO effect: levodopa, amantadine, benzhexol (trihexifenidyl), budipine, selegeline (Deprenyl), metoprolol, propranolol en primidon NO interference expected from dopamine receptor-agonists 123 I-Ioflupane SPECT Procedure Nigrostriatal Pathway Striatum Thyroid blockade Single i.v. injection of 123 I-Ioflupane (3-5 mci) SPECT Effect of rmal Aging on Specific [ 11 C]DTBZ DV tot in the Putamen 3-6 h. Gamma cameras : Two-headed or three-headed Collimators: high resolution or fan beam Photopeak 159KeV; Energy Window ±10% Minimum of 750k counts/slice Substantia Nigra SPECIFIC DV tot 2.5 2.0 1.5 1.0 0.5 0.0 20 30 40 50 60 70 AGE (yr) DV tot = 1.432-0.011[age] r = 0.53, p = 0.04. Frey et al. Ann Neurol 1996; 40:873. Clinical level Parkinsonian Signs in the Elderly Parkinsonism - tremor - rigidity -bradykinesia - postural abnormalities -gait - cognitive decline - autonomous signs - speech disturbance >> 90% Idiopathic Parkinson s Disease Multiple System Atrophy PSP Essential tremor Vascular Toxic Corticobasal degeneration Wilson s disease 467 residents > 64 years > 2 specified parkinsonism features Age BK Gait Rigid Tremor Parkinsonism 65-74 y 11% 13% 19% 19% 15% 75-84 y 21% 28% 30% 24% 30% 85 y + 37% 52% 44% 30% 52% Bennett et al. NEJM 1996;334:71-6. 3

Parkinson s Disease Second most prevalent neurodegenerative disorder Prevalence 1-2 % (> 65 y) Etiology :? Genetic factors N PM Parkin Alpha-synuclein Ubiquitin C hydrolase L1 Environmental Oxidative stress Protein aggregation in SNc common to all forms 46 IPD and... 26 vascular disease 10 Alzheimer-type THE BRAIN BANK : 100 CASES Hughes et al, JNNP 1992 76 histological IPD Tatsch, EANM 2000 30 IPD only 24 not IPD 6 PSP 5 MSA 3 Alzheimer 3 lacunar 1 post-encephalitis 1 ET Same numbers : Rajput et al, J Can Neurol Sci 1991 BUT : Hughes, Lees et al (Brain 2002): Accuracy in specialist movement disorder service > 85 % for IPD, MSA and PSP Features Improving Accuracy in PD Hughes et al Neurol 1992; 42: 1142-6 Diagnostic Accuracy: Specialist and Generalist Initial Diagnosis PD n=131 Specialist n-specialist n=97 n=34 Brain Bank Criteria + Asymmetric onset + atypical features + possible cause for other PS Diagnostic accuracy 93% But 32% of pathologically proven PD not identified Confirmed Refuted Confirmed Refuted n=86 (89%) n=11 (11%) n=25 (74%) n=9 (26%) Initial Diagnosis not PD n=69 Specialist n-specialist n=26 n=43 Confirmed Refuted Confirmed Refuted n=20 (77%) n=6 (23%) n=34 (79%) n=9 (21%) Schrag et al; JNNP 2002;73:529-534. Difficult Clinical Cases Diagnostic Revision in PD Study Type n error rate CALM-PD 2002 β-cit SPECT 82 4% Benamer et al 2003 FP-CIT SPECT 38 13% Real-PET 2003 18 F-Dopa PET 186 11% Ell-dopa 2003 β-cit SPECT >100 14% Patients with a tremor dominant disorder Long-standing tremor-dominant disorder, considered essential tremor but with features raising uncertainty Tremor treatment: poorly tolerated Antiparkinson treatment: little effect Drug-induced or unmasked PD Patients with current or recent drug R/ known to cause drug-induced parkinsonism Persistence of features after stopping or amending treatment Or clinical features more suggestive of idiopathic PD Patients with multiple pathology Patients with co-existent medical conditions which affect interpretation of the movement disorder - small vessel cerebrovascular disease - depression / anxiety - chronic obstructive pulmonary disease - osteoarthritis and osteoporosis 4

Summary: Clinical Diagnosis of PD A majority of cases can be diagnosed clinically Therapy response and monitoring over time improves diagnostic accuracy Visual Assessment of SPECT image Abnormal rmal Type 1 Type 2 Type 3 Clinical Aspects of Early Diagnosis PD has a long pre-symptomatic phase Early clinical features are mild / subtle Clinical monitoring / therapy trial over 6 months to 2 years Average time to confirmed and accepted diagnosis is 18 months 123 I-Ioflupane SPECT Yielding (Uncertain diagnosis) n= 33 Rate True Positive 100% True Negative 92% False Negative 8% (Booij et al. Eur J Nucl Med 2001, 28: 266-272) Visual assessment n=158 PD, 27 ET, 35 HV Institutional read Consensus Blindedread Sensitivity for PD 97% 95% Specificity for ET 100% 93% (Benamer et al. Movement Disorders 2000, 15: 303-510) Pirker. Mov Disoder 2003;18:S43-51. STUDY POPULATION Patients with Clinically Uncertain Parkinsonian Syndrome Marshall & Grosset. Mov Disoder 2003;18:22-7. Patients recruited (written informed consent) 125 Patients included 120 Evaluable Patients 118 DaTSCAN not performed 5 Prohibited medications 2 Demographics & Clinical Symptoms Number of patients 118 Sex Male/female 59/59 Race Caucasian/others 116/2 Age (years ±SD) 65.5 ±11.2 Unilateral symptoms 62% Bradykinesia 69% Tremor 74% Rigidity 63% Postural instability 36% Exclusion criteria: Diagnosed PS but clinical uncertainty between PD, PSP and MSA Medications suspecting to interact with 123 I-Ioflupane uptake History of drug abuse Others 5

Results of DaTSCAN image versus initial suspected clinical diagnosis Final diagnosis vs. results of DaTSCAN 80% 60% 40% 20%? 36% 63% 46%? 54% 32% 68% rmal Abnormal %of patients 100% 80% 60% 40% 100% 94% normal(44) abnormal(73) 59% 41% 0% PS (n=66*) n-ps (n=26) Inconclusive (n=25) * in one patient the image was not interpretable Initial diagnosis 20% 6% 0% 0% PS (n=62)* non-ps (n=33) Inconclusive (n=22) Final diagnosis * in one patient the image was not interpretable Clinical Impact of 123I-Ioflupane (DaTSCANTM) SPECT Impact on diagnosis in 109/118 patients (92.4%): Change initial diagnosis: 53 (45%) More confident with initial diagnosis: 56 (47%) Change to other than PS 25% Change to PS 20% impact on diagnosis 8% PS supported 31% Confidence in PS: 63.9±19.7 to 90.5±13.3%, p<0.0001 Other than PS supported 16% Confidence in PS: 41.1± 24.2 to 8.7±13.6%, p<0.0001 Choice Target Cohort:?P S Test Use of DatSCAN Analytical Model (simple version) Diagnostic outcome +ve:?ps -ve:?et Treatment selection PS therapy ET therapy True result plus Consequences TP: PS Benefit, AEs FP FN: PS TN benefit, AEs benefit Benefit PS Benefit, AEs PS therapy Other benefit, AEs use of DatSCAN PS benefit ET therapy Other Benefit PS = Parkinson syndrome ET = Essential tremor TP/TN = True Positive/True Negative FP/FN = False positive/ False Negative Costs of Diagnosis, Treatment and Adverse Events ( ) Final Results CURRENT DatSCAN DIFF Current diagnosis and treatment Current diagnosis and treatment 123I-FP-CIT SPECT 1 year PD drug treatment first line 1 year PD drug treatment second line 1 year PD specialist visits Follow-up diagnosis 6 months follow-up diagnosis over 2 5 years treatment 6 months ET drug treatment 6 months Costs of treating adverse events Dyskinesia Psychosis Orthostatic hypotension 216 900 1,625 1,819 170 86 162 131 230 1,584 2,172 1,115 Total cost Adequately treated yrs Cost per adequately treated year Prevalence of PS 39% 46% 53% 59% 66% Total cost current 6,253 6,359 6,465 6,556 6,663 ATY current 1.753 1.876 2.000 2.105 2.228 Total cost DaTSCAN 5727 6150 6573 6936 7360 6464 1.998 3235 ATY DaTSCAN 3.369 3.383 3.397 3.408 3.422 Diff. cost -526-209 108 380 697 6569 3.397 1934 Diff. ATY 1.616 1.507 1.397 1.303 1.194 105 1.398 74.8 Cost per ATY -325-139 77 291 584 Van Laere et al. Eur J Nucl Med Mol Imaging 2008;35:1367-76. 6

SPECT, Diagnosis and Management Results from the Registry Study Detection of Preclinical PD Hemiparkinsonism: striatal DAT binding : 39% contralateral, 28% ipsilateral (Staffen W et al. Nucl Med Commun 2000;21:417) MPTP: (Calne DB et al. Nature 1985;246) Twins: asymptomatic co-twins of affected PD patients, FDOPA 53% MZ; 13% DZ (Burn DJ et al. Neurology 1992;41:1894) Susceptibility in familial PD: 34% asymptomatic relatives FDOPA < 2.5 SD (Piccini P et al. Ann Neurol 1997;41:222) Essential tremor: 20-33% PD (Brooks DJ et al. Neurology 1992;29:673) Van Laere et al. Eur J Nucl Med Mol Imaging 2008;35:1367-76. Annual Percentage Changes in Striatal β-cit Uptake in PD Models of Disease Progression References Change (%) Pat. (N) Pirker et al., 2002 mean disease duration 9.2 ± 2.6 yrs 2.4 ± 9.6 12 mean disease duration 2.4 ± 1.5 yrs 7.1 ± 7.1 24 Marek et al., 2001 11.2 ± 8.3 32 Chouker et al., 2001 6.6 8 Staffen et al., 2000 5.6 15 Seppi et al., 2001 9 Contralat. to affected limb 5.7 ± 3.8 Ipsilateral to affected limb 6.4 ± 3.5 Poewe & Scherfler. Mov Disoder 2003;18:S16-21. % Residual DA neurons in the SN 100 % 90 % 80 % 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % Threshold for clinical symptoms Pre sympto matic Lifetime Symptomatic (H&Y stage) st I st II st III st IV st V Imaging Outcome Measures to Evaluate Efficacy of Putative Neuroprotective Agents Imaging of the presynaptic DA system: Indications 1. Parkinson Disease - PD: establishment of early and preclinical diagnosis - PD: assessment of the severity of disease - PD: measuring disease progression - PD: monitoring neuroprotection/neurorescue Pavese & Brooks. Biochim Biophys Acta 2008; in press. 2. Differential diagnosis of parkinsonian syndromes 3. Assessment of LBD 7

DAT SPECT presynapt. dopamin. deficit Essential Tremor PD Confirmation / exclusion of parkinsonian syndromes Presence of a presynaptic dopaminergic deficit PSP MSA 1.5 / 100.000 4.0 / 100.000 ΔΔ Parkinsonism with Presynaptic DA ligands Clinical status and presynaptic DA integrity [ 123 I]β-CIT Binding and Clinical Status (n) All Stage I Stage II Stage III Control 6.0 ± 1.6 (11) IPD 3.4 ± 0.8 (58)* 3.9 ± 0.5 (9) 3.6 ± 0.6 (25) 3.0 ± 0.8 (24) SPD 5.5 ± 1.4 (29)* 4.8 (1) 6.2 ± 1.1 (14)* 4.7 ± 1.3 (14)* Staffen et al. Nucl Med Commun 2000;21:417. + vertical gaze palsy + postural instability + dysphagia + subcortical dementia + cerebellar signs + autonomic dysfunction Topography of the striatal DA deficit Striatal Projections & Parkinsonism DA Imaging in sopca V3 (ROI 1 - ROI 4) 6 4 2 0 rmals PD PSP Mesa C et al. Eur J Nucl Med 1998;25:1270. Striatal FDA Uptake, Concurrent and Subsequent Vital Status Patient FDOPA (91) Parkinsonism(91) Parkinsonismlater #1 Unknown #2 #3 N #4 #5 #6 #7 N #8 #9 #10 by 1SD Shrag et al. Ann Neurol 1998;44:151. Corticobasal Degeneration Unilateral parkinsonism and: dyspraxia cortical sensor. deficits alien limb syndrome myoclonus dementia Striatum Presynaptic site Nigrostriatal Pathway no levodopa response rapid progression Substantia Nigra Unilateral atrophy of the central region in > 50% Postsynaptic site 8

Discriminative Power IPD / MSA (/ PSP) Presynaptic binding - 18 F-dopa and 123 I-beta/FP-CIT - discrimination in 50-60% of patients (Pirker et al., Mov Disord 2000) * Perfusion and metabolism - 18 FDG PET and 99m Tc-ECD SPECT - posterior lentiform nucleus hypometabolism/perfusion in 70-80% of patients (Brooks, Brain Mapping 2000; Bosman et al. EJNM 2002) Postsynaptic binding 11 C-raclopride : highest discriminating capacity : up to 100% (Antonini et al., Brain1997, Ghaemi et al JNNP 2002) * 123 I-IBZM : sensitivity and specificity 70-80% (Larisch & Klimke, Nuclearmedizin 1998) * higher if combined with presynaptic studies? MRI Signal Changes and Parkinsonism Signal Changes within the Putamen in 90 Patients with Parkinsonism of Various Origins MRI Only Hypointense & (Putamen) rmal Hypointense Hyperintense Total MSA 1 5 9 15 PSP 6 4 0 10 PD 59 6 0 65 Kraft E et al. Arch Neurol 1999; 56:225. Hypointense putaminal changes - poor response to DA treatment - clearly related to normal aging - due to iron? gliosis? calcification? Hypo- & hyperintense putaminal signal : specific for MSA, but tardive * Most of these studies use post-hoc values and were not cross-validated! Clinical Pointers for Structural Imaging in Parkinsonism Secondary Parkinsonism CO Intoxication Putaminal hemorrhage Vascular risk factors / markers Predominantly lower body parkinsonism, usually symmetrical Features suggesting normal pressure hydrocephalus Abnormally prolonged asymmetry Adachi M et al. AJNR 1999;20:1500. Pseudo PS Subcortical arteriosclerotic encephalopathy (SAE) rmal pressure hydrocephalus (NPH) difficulties with balance upper limbs intact lower body parkinsonism important ΔΔ, treatable!! Presynaptic site neopterin Tyr TH Dopa DOPA Response Dystonia GTP GCH-I Dihydroneopterin triphosphate 6-PPH synthase 6-Pyruvoyltetrahydropterin - Tetrahydrobiopterin Sepiapterin reductase Quinonoid Dihyhydrobiopterin NAD + DHPR NADH + H + Juvenile PD Jeon BS et al. Ann Neurol 1998. 9

Drug-Induced Parkinsonism Common, often underdiagnosis (25-35% PS) More in females and elderly Clinical aspect: - Bucco-linguo-masticatory syndrome, focal dystonia, stereotypies, akathisia - Tremor in 29%, asymmetry in 2/3 - Within few days of several years, not always reversible Drugs: - neuroleptiques - few calcium-channel blockers (flunarizine, cinnarizine) - DA-depleting agents (reserpine, tetrabenazin) Psychogenic Parkinsonim 1.9-6.4% PS More in young females Unusual movement disorder: Sudden onset, may be trigger by minor injury Complex tremor rigidity=resistance Fluctuation Most, very effective dopaminergic treatment Tolosa et al. Mov Disoder 2003;18:S28-33. Tolosa et al. Mov Disoder 2003;18:S28-33. Differential Diagnosis of Dementia Vascular dementias Multi-infarct dementia Binswanger s disease Vascular dementias and AD Other dementias Frontal lobe dementia Creutzfeld-Jakob disease Corticobasal degeneration Progressive supranuclear palsy others Dementia with Lewy bodies Parkinson s disease Diffuse Lewy body disease Lewy body variant of AD AD and dementia with AD Lewy bodies 5% 10% 65% 5% 7% 8% Small et al. JAMA 1997;278:1363-71 American Psychiatric Association. Am J Psychiatry 1997;154:1-39 Morris JC. Clin Geriatr Med 1994;10:275-6. Diffuse Lewy Body Disease Lewy bodies in subcortical, allocortical, and neocortical structures Pure form or associated in conjunction with AD 13-26% dementia Clinical features: fluctuating cognitive impairment (Ss 75%; Sp 79%) visual hallucinations parkinsonism Adverse effects of typical antipsychotics; 2 atypicals recommended: Quetiapine (Seroquel ), Clozapine (Clozapine, Leponex ) Cognition may differentially benefit from AChE inhibition Subtle bradykinesia/rigidity may benefit from antiparkinsonian therapy; avoid DA agonists Dementia Subtypes in FDG PET Walker et al. Lancet 1999;354:646-7. Minoshima et al., 2002. 10

DAT Imaging With presynaptic deficit Neurodegenerative PS Parkinson s disease Multiple system atrophy Progressive supranuclear palsy Cortico basal degeneration DLBD Without presynaptic deficit Parkinsonian syndromes Psychogenic PS Drug induced PS Tremor syndromes essential tremor Psychogenic Drug induced cerebro-vascular Walker et al. J Neurol Neurosurg Psychiatry 2007;78:1176-81. Thank you for your attention... 11