Quantification in Nuclear Medicine imaging (Parkinson s and Alzheimer s disease)

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1 Quantification in Nuclear Medicine imaging (Parkinson s and Alzheimer s disease) Kosmas Badiavas MSc, PhD Medical Physicist 3 rd Nuclear Medicine Department Aristotle University of Thessaloniki

2 Nuclear Medicine imaging in Parkinson s disease SPECT & PET Nuclear Medicine imaging in Alzheimer s disease PET

3 Single Photon Emission Tomography SPECT

4 SPECT/CT Optima NM CT 640

5 Positron Emission Tomography (PET) PET-camera i.v. injection

6 The striatum Kερκοφόρος πυρήνας (caudate nucleus) Κεφαλή Ουρά Φακοειδής πυρήνας (lentiform nucleus) Κέλυφος (putamen)

7 Nuclear medicine imaging radiopharmaceuticals in Parkinson s disease (SPECT και PET) SPECT 123Ι-Ioflupane (DaTSCAN) Parkinson s disease Vs Essential tremor (Ιδιοπαθής Τρόμος) 123Ι-IBZM Parkinson s disease Vs Parkinson Plus syndromes

8 Various radiopharmaceuticals same image Tatsch K. Imaging of the dopaminergic system in parkinsonism with SPET. Nucl Med Communications 2001;22:

9 Datscan - IBZM DaTSCAN ( 123 I-FPCIT) 123 I-IBZM

10 DaTSCAN

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12 Αρχή λειτουργίας γ-camera

13 ΡΕΤ with 11 C raclopride * Used usually as a template Kas A, Payoux P, Habert MO, Malek Z, Cointepas Y, El Fakhri, et al. Validation of a standardized normalization template for Statistical Parametric Mapping analysis of 123 I-FP-CIT images. J Nucl Med 2007;48: Lokkegaard A, Werdelin LM, Friberg L. Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand. Eur J Nucl Med 2002;29:

14 The Alderson striatal head phantom (RSD)

15 Visual assessment is the main diagnostic method however Quantification is proposed by international organizations and might Shift method s sensitivity Used for patients follow up Used for multicenter studies

16 Diagnosis in dopaminergic system studies with nuclear medicine methods Visual assessment: Evaluation of the full and symmetrical uptake of the radiopharmaceutical. Semiquantitative methods: Comparison between the uptake in Regions of Interest (ROIs) and background taken in a non-specific uptake area inside the brain parenchyma. Expressed as the ratio between the specific and nonspecific uptake.

17 The EANM guidelines

18 From quantification using compartmental analysis and tracer kinetic modeling to semiquantification Quantification Semiquantification Ratio between specific and non-specific binding Multiple arterial blood sampling is needed

19 More than 40 citations ( )

20 Categorization of semiquantification methods Κλασσικές μέθοδοι ποσοτικοποίησης (classic quantification methods) Προηγμένες αυτοματοποιημένες μέθοδοι (advanced automated quantification methods) Μέθοδοι στατιστικής ανάλυσης βασισμένες στα στοιχεία εικόνας (pixel-based statistical analysis methods) Badiavas K, Molyvda E, Iakovou I, Tsolaki M, Psarrakos K, Karatzas N. SPECT imaging evaluation in movement disorders: far beyond visual assessment. Eur J Nucl Med Mol Imaging 2011;38:

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22 Categorization of quantitative methods Classical methods Manual ROIs placement ROIs placement after SPECT-MR image fusion or template copy-paste Partial Volume Effect (PVE) avoidance Automated software packages Advanced automated methods Statistical analysis pixel or voxel based Using Statistical Parametric Mapping (SPM) Using added software on top of SPM and/or MATLAB Using other statistical analysis pixel or voxel based software Badiavas K, Molyvda E, Iakovou I, Tsolaki M, Psarrakos K, Karatzas N. SPECT imaging evaluation in movement disorders: far beyond visual assessment. Eur J Nucl Med Mol Imaging 2011;38:

23 Classic Quantitative Indeces PU=(P-B)/B putamen uptake πρόσληψη στον φακοειδή πυρήνα CU=(C-B)/B caudate uptake πρόσληψη στον φακοειδή πυρήνα SBP={[(C+P)/2]-B}/B striatum binding potential δυναμικό σύνδεσης στο ραβδωτό σώμα PCR=P/C putamen to caudate ratio λόγος της πρόσληψης στον φακοειδή προς την πρόσληψη στον κερκοφόρο πυρήνα

24 Manual placement of Regions of Interest Manual ROI placing Φύλλο υπολογισμού ποσοτικών δεικτών (Excel spreadsheet)

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27 The QuantiSPECT software package An automated software package for Personal Computer The two box method Fleming JS, Bolt L, Stratford JS and Kemp PM. The specific uptake size index for quantifying radiopharmaceutical uptake. Phys Med Biol 2004;49:N227-N234 The three box method Costa DC, Walker Z, Dizdarevic S, Ioannides C, Gacinovic S, Walker RW, et al. Striatal binding of FP-CIT: a simple method to separate Parkinson's disease patients and normal controls (abstract). Eur J Nucl Med 1998;25:1069 The crescent method Lokkegaard A, Werdelin LM, Friberg L. Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand. Eur J Nucl Med 2002;29:1623-9

28 Το πακέτο λογισμικού QuantiSPECT The two box method (Fleming, 2004) The three box method (Costa, 1989) The crescent method (Lokkegaard, 2002)

29 The QuantiSPECT environment PC-based Feed raw data or DICOM images raw data reconstruction Chang attenuation correction capability 3 semiquantification methods patient database creation capability find one like capability Report generation

30 Ποσοτικοί δείκτες στη μέθοδο two box SBI=[(C+C b )/V v ]/V s specific binding index C : total counts in striatum ROI C b : total counts in bkg / bkg region V v : striatum volume ROI V s : standard striatum volume (11.2ml) Πλεονέκτημα: αποφυγή φαινομένου μερικού όγκου Partial Volume Effect (PVE)

31 Η μέθοδος two box στις εικόνες της γ-camera Απαιτεί την τοποθέτηση δυο υπερμεγεθών περιοχών ενδιαφέροντος Με αλγόριθμο γίνεται αυτόματη τοποθέτηση της περιοχής υποβάθρου Ειδικός λόγος σύνδεσης (Specific Binding Index - SBI) SBI = [ ( C/C b ) / V v ] / V s

32 Ποσοτικοί δείκτες στη μέθοδο three box TBPI={[C-(BxV)]/(BxV)}x100 total potential binding index C : total counts in striatum ROI B : average counts per voxel in bkg area V : striatal ROI volume Πλεονέκτημα: αποφυγή φαινομένου μερικου όγκου Partial Volume Effect (PVE)

33 Η μέθοδος three box στις εικόνες της γ-camera Απαιτεί την τοποθέτηση δυο υπερμεγεθών περιοχών ενδιαφέροντος και μιας τρίτης περιοχής ως περιοχή υποβάθρου Δείκτης ολικού δυναμικού σύνδεσης (Total Binding Potential Index - TBPI) TBPI = {[C-( BxV)] / (BxV)}x100

34 Ποσοτικοί δείκτες στη μέθοδο crescent SU=(S-B)/B striatum uptake PU=(P-B)/B putamen uptake PCR=P/C putamen to caudate ratio S : average striatum uptake P : average putamen uptake B : average bkg uptake Πλεονέκτημα: template ROIs

35 Η μέθοδος crescent στις εικόνες της γ-camera Απαιτεί την τοποθέτηση τριών περιοχών ενδιαφέροντος Πρόσληψη στο ραβδωτό σώμα (Striatum Uptake - SU) SU = (S-B) / B Πρόσληψη στον φακοειδή πυρήνα (Putamen Uptake PU) Λόγος φακοειδή προς κερκοφόρο πυρήνα (Putamen to Caudate Ratio PCR)

36 Διόρθωση εξασθένησης (First-order Chang attenuation correction)

37 Phantom - two box method Non AC AC

38 Phantom - three box method Non AC AC

39 Phantom - crescent method χωρίς διόρθωση για εξασθένηση μετά τη διόρθωση για εξασθένηση

40 Phantom - manual method Non AC AC

41 The ENC-DAT project European Association of Nuclear Medicine (EANM) EANM Research Ltd. Calibration service of gamma cameras for ENC-DAT research project creating a normal database European database of [ 123 I]FP-CIT (DaTSCAN) SPECT scans of healthy controls Aim : to calculate the true to measured striatal to background uptake and derive calibration curves, whose slope gives the recovery coefficient for the respective camera system so that data can be directly compared to the one in the normal s database

42 ΕΑΝΜ 2008 (Munich, Germany)

43 ΕΑΝΜ 2010 (Vienna, Austria)

44 ΕΑΝΜ 2010 (Birmingham, UK)

45 ΕΑΝΜ 2012 (Milan, Italy)

46 ΕΑΝΜ 2013 (Lyon, France)

47 ΕΑΝΜ 2014 (Gothenburg, Sweden)

48 Βάση φυσιολογικών δεδομένων 27 εξεταζόμενοι που δεν βρέθηκαν να πάσχουν από τη νόσο του Parkinson ή άλλη εξωπυραμιδική συνδρομή (11 άνδρες, 16 γυναίκες, ηλικίες 66±14 έτη)

49 Βάση δεδομένων ασθενών 61 ασθενείς (36 άνδρες, 25 γυναίκες, ηλικίες 68.8±8.7 έτη)

50 Για τυχαία επιλεγμένους εξεταζόμενους με γνωστή τελική διάγνωση συγκρίθηκαν τα αποτελέσματα των μεθόδων 15 εξεταζόμενοι (9 άνδρες, 6 γυναίκες, ηλικίες 68.7±9.8 έτη) Αποτελέσματα UPDRS test που συμπληρώθηκε για τους 15 ασθενείς

51 Για τυχαία επιλεγμένους εξεταζόμενους με γνωστή τελική διάγνωση συγκρίθηκαν τα αποτελέσματα των μεθόδων 15 εξεταζόμενοι (9 άνδρες, 6 γυναίκες, ηλικίες 68.7±9.8 έτη)

52 Για τυχαία επιλεγμένους εξεταζόμενους με γνωστή τελική διάγνωση συγκρίθηκαν τα αποτελέσματα των μεθόδων 15 εξεταζόμενοι (9 άνδρες, 6 γυναίκες, ηλικίες 68.7±9.8 έτη) *Οι ακέραιοι αριθμοί δικαιολογούνται από το μικρό δείγμα περιστατικών **Λόγω του μικρού δείγματος των περιστατικών, τα αποτελέσματα παρέχουν απλά μια εκτίμηση για την ευαισθησία και την ειδικότητα κάθε μεθόδου

53 Βάση φυσιολογικών δεδομένων 27 εξεταζόμενοι που δεν βρέθηκαν να πάσχουν από τη νόσο του Parkinson ή άλλη εξωπυραμιδική συνδρομή (11 άνδρες, 16 γυναίκες, ηλικίες 66±14 έτη) Badiavas K, Iakovou I, Molyvda E, Tsolaki M, Psarrakos K, Karatzas N. Creation of a customized Normal Database for 123I-FP-CIT SPECT studies in a major Nuclear Medicine department in Northern Greece. Eur J Nucl Med Mol Imaging 2010; 37 Suppl 2:S399.

54 Το περιβάλλον του λογισμικού EXINI-dat (EXINI Diagnostics AB, Sweden)

55 Το λογισμικό BRASS στο σταθμό εργασίας Hermes (Hermes Medical Solutions, Sweden)

56 Zubal et al. (Objective Striatal Analysis - OSA)

57 MRI image Phantom MRI

58 Phantom MRI Spin echo T1-weighted 3D-MPRAGE T1-weighted

59 Magnetic Resonance Imaging (MRI)

60 Patient DaTSCAN and MRI two box method

61 MRI-SPECT automatic interactive image registration

62 MRI-SPECT image registration algorithm

63 Automatic image registration

64 Statistical Parametric Mapping Seppi K, Scherfler C, Donnemiller E, et al. Topography of dopamine transporter availability in Progressive Supranuclear Palsy: A voxelwise [ 123 I]β-CIT SPECT analysis. Arch Neurol 2006; 63:

65 SPM (Statistical Parametric Mapping) Flow chart for SPECT MRI image registration normalized in MNI space

66 The FP-CIT or IBZM tool (Buchert, 2006) Pixel based statistical analysis MATLAB scripts toolbox Statistical Parametric Mapping (SPM) Stereotactic Normalization DaTSCAN Buchert R, Berding G, Wilke F et al. IBZM tool: a fully automated expert system for the evaluation of IBZM SPECT studies. Eur J Nucl Med Mol Imaging 2006;33:

67 BASGAN (Italy)

68 The basal gaglia (recostruction based on Talairach atlas) Calvini P, Rodriguez G, Inguglia F, Mignone A, Guerra UP, Nobili F. The basal gaglia matching tools package for striatal uptake semi-quantification: description and validation. Eur J Nucl Med Mol Imaging 2007;34:

69 The Future? (Artificial Neural Networks) e.g. PD / ΕΤ Decision making Artificial Neural Network flow chart Habraken JB, Booji J, Slomka P et al. Quantification and visualization of defects of the functional dopaminergic system using an automated algorithm. J Nucl Med 1999;40:

70 Alzheimer s disease The amyloid hypothesis that postulates that β-amyloid accumulation and plaque formation in the brain is the initial event in the pathogenesis of AD and that this occurs long before first clinical symptoms emerge is widely accepted. Jack Jr CR, et al. Lancet Neurol 2010;9:

71 The radiopharmaceuticals Pittsburgh compound B (ΡΙΒ) as 11 C ( 11 C-PIB) 20min half-life (on-site cyclotron needed) 18 F (110min half-life) 18 F-florbetapir 18 F-florbetaben 18 F-flutemetamol

72 β amyloid quantification The first tries for the quantification of the β-amyloid deposition in human brain with the radiopharmaceutical 11 C-PIB were again based, like in the quantification of the uptake in the basal gaglia in Parkinson s disease case, in dynamic acquisition, multiple arterial sampling and compartmental modeling. For the first time in 2005 the quantification method, based on the calculation and the evaluation of the ratios between target-areas and a reference region in a late sum image, was proposed and since then became routine.

73 β amyloid quantification These ratios are commonly called Standardized Uptake Value Ratios (SUVRs). The reference area usually is placed in the gray matter of the cerebellum but in some cases all cerebellum or the pons are being used as well. For the categorization of the images as positive or negatives, through the use of quantitative data, setting a threshold is a prerequisite. Receiver Operating Curve (ROC) analysis and statistical methods have been proposed for setting up the threshold. Other approaches use healthy individuals data for the creation of a SUVRs reference base, based on which the threshold value can emerge.

74 β amyloid quantification The accuracy of the placement and the need for repetitiveness of the ROIs for different examinations and patients, inspired the use of various methods. The initial approach was again based on manual ROIs definition either on the ΡΕΤ image or on the co-registered and fused MRI image. As manual ROIs placement is time consuming and subjective, automated methods have been proposed once more. A typical approach is using Statistical Parametric Mapping (SPM) in order for data to be normalized to the Montreal Neurologic Institute (MNI) map.

75 β amyloid quantification Alternatively, a segmentation software acting upon the MRI image and the transfer of the ROIs on the PET image can be used. Finally, in order to avoid the need for recent digital MRI images of the patient, advanced automated software packages for clinical use, not necessitating a recent MRI scan, are now available (PET-only methods). The two most common image analysis methods, namely, the classical ROIs placement (although fully-automated) method and the voxel-wise analysis will be now shortly described.

76 The classical ROIs placement method Let us assume the nuclear medicine department owns one of the many specialized image analysis software. After the PET and MR imaging of the patient, each PET image is co-registered to the corresponding T1-weighted MR image after the T1-weighted MR images have been spatially normalized to the Montreal Neurological Institute (MNI) template. A large number of Volumes of Interest (VOIs) e.g. 8, are automatically selected depending on the algorithm of the automated software. The whole cerebellum is a good example of the reference region used for calculating the Standardized Uptake Value Ratios (SUVRs) to obtain the final spatially normalized PET SUVR image for the specific patient. The average SUVR from the seven, in our example, cerebral cortical VOIs (one of the eight VOIs in our example is the reference area) is taken to be the global cortical SUVR for the patient.

77 The Voxel-wise analysis Voxel-wise analysis is performed with one of the many SPM versions (Wellcome Department of Cognitive Neurology, Institute if Neurology, London,UK) e.g. SPM5 in one of the many Matlab versions (MathWorks Inc. Natick, MA) e.g. Matlab 2012a. The spatially normalized PET SUVR images are smoothed using an isotropic kernel. Luckily, the SUVR images for voxel analysis are same as those normalized by the mean value of the whole cerebellum in the previous VOI quantitation described. This is the main reason why many departments use both methods as complementary. Voxel-wise two sample t tests are used to compare the healthy controls and each patient using the amyloid SUVR images. SPM images are usually examined using an uncorrected threshold of P<0.005 and an extent threshold of 100 voxels.

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