The Role of Dopamine Transporter Imaging in Movement Disorders
Claire Henchcliffe MD DPhil Vice Chair for Clinical Research Director, Weill Cornell Institute for Parkinson’s Weill Cornell Medical Center New York NY
American Society of Neuroimaging 38th Annual Meeting DISCLOSURES
Advisory board membership: Acadia, Teva Pharmaceu cal Industries, USWorldMeds Speakers bureau member: Acadia, GE, IMPAX, Lundbeck, Teva Pharmaceu cal Industries Consul ng: Peptron Research funding: Biogen, Dana Founda on, Kaneka, Michael J Fox Founda on, NINDS, Parkinson Disease Founda on, Solomon Family Founda on, Starr Founda on Editorial compensa on: Neuroalert
American Society of Neuroimaging 38th Annual Meeting BACKGROUND: THE DOPAMINE TRANSPORTER
• Transmembrane dopamine transporter (Na/Cl) • Primary clearance mechanism for intrasynap c dopamine (except prefrontal cortex) • Cocaine is a DAT blocker • Amphetamine is a compe ve dopamine reuptake inhibitor ac ng at the DAT
American Society of Neuroimaging Penmatsa et al (2013) Nature 503, 85-91 38th Annual Meeting DOPAMINE TRANSPORTER LOCALIZATION
Cortex (e.g. motor, premotor, supplementary motor, prefrontal, entorhinal, Concentrated in caudate, putamen perirhinal, insular, visual) Scattered in GPe/GPi Substantia nigra/VTA
American Society of Neuroimaging Ciliax et al (1999) J Compar Neurol 409: 38-56 38th Annual Meeting NEURODEGENERATION AND DOPAMINE • Dopaminergic neurons of the substan a nigra degenerate and die in mul ple disorders, including: • Parkinson’s disease • Demen a with Lewy bodies • Parkinson’s Plus syndromes • Mul ple system atrophy • Progressive Supranuclear Palsy • Cor cobasal syndrome • Others (not primary feature): • Mitochondrial disease • Spinocerebellar ataxias (SCA2, 3, 6) • Hun ngton’s disease American Society of Neuroimaging Dauer and Przedborski (2003) Neuron 39, 889-909 38th Annual Meeting IMAGING AGENTS FOR THE NIGROSTRIATAL SYSTEM
American Society of Neuroimaging Cummings et al (2011) Brain:134-3146-3166 38th Annual Meeting EXAMPLES OF DOPAMINE TRANSPORTER LIGANDS
Ioflupane (123I-FP-CIT) altropane
American Society of Neuroimaging Edmond et al (2008) CNS Neurosci Ther 14: 47-64 38th Annual Meeting PET DEMONSTRATES LOSS OF DAT IN PARKINSON’S DISEASE
A B
PE2i
A. 75 year old healthy woman B. 76 year old man with PD for 8 years
American Society of Neuroimaging 38th Annual Meeting
[11C]PE2i:**Le-*4*x*4*panel:*75*y.o.*healthy*female;*right*4*x*4*panel:*76*[11C]PE2i:**Le-*4*x*4*panel:*75*y.o.*healthy*female;*right*4*x*4*panel:*76*y.o.*male*with*PD*x*8* y.o.*male*with*PD*x*8* years.*Note:**images*are*not*normalized*for*the*administered*dose.*years.*Note:**images*are*not*normalized*for*the*administered*dose.* synthesis imaging has some drawbacks, and postsynaptic TABLE 1 dopamine receptor imaging does not help in diagnosing PD Approval Year for Clinical Use of Radioligands for patients because PD pathology is on the presynaptic side. DAT Imaging 18 L 18 F- -6-fluoro-3,4-dihydroxyphenylalanine ( F-DOPA) is Radioligand United States Elsewhere a representative radioligand for dopamine synthesis and reflects dopaminergic as well as noradrenergic neuronal 123I-b-CIT (DOPASCAN; MAP — Europe*, Japan* function. 18F-DOPA imaging involves multiple steps in- Medical Technologies Oy) 123I-FP-CIT (DaTSCAN) 2011 2000 in Europe, cluding the uptake and conversion of fluorodopa to fluoro- 2011 in Korea dopamine (15). 18F-DOPA uptake is not a direct measure of 18F-FP-CIT — 2008 in Korea nigral cell count (15). Furthermore, compensatory upregu- 99mTc-TRODAT-1 — 2005 in Taiwan latory changes of dopamine synthesis rate might occur in PD, hindering accurate measurement (15). DATs are known *Before 123I-FP-CIT, but exact date unknown. to be downregulated in PD patients as an early response to decreased synaptic dopamine concentration (16). DAT im- aging might be a more sensitive indicator of dopaminergic physician licensure and clinic registration are mandatory 123 degeneration than 18F-DOPA (17). (16). The recommended dosage of I-FP-CIT is 111–185 MBq (3–5 mCi), typically 185 MBq (5 mCi). The effective RADIOLIGANDS FOR DAT IMAGING AND THEIR dose of a single 123I-FP-CIT brain SPECT scan is estimated DAT LIGANDSCLINICAL AVAILABILITY IN CLINICALto be 2.3–4.4 mSv, which is similar to a chest USE CT dose (16). There are several radioligands for DAT imaging. Among 123I-FP-CIT is taken up rapidly in the human striatum, and DAT imaging methods, SPECT using 123I-b-CIT, 123I-FP- CIT, or 99mTc-TRODAT-1 has been most widely used and approved for clinical use in different countries. 123I-FP-CIT is not the first of its kind but has recently become the first and only U.S. FDA–approved radioligand for DAT imaging 123 for clinical purposes. This newly approved radioligand ac- • I-FP-CIT US approval tually was already authorized for clinical use in July 2000 in Europe (18), for the differential diagnosis of patients 2011 (Europe 2000) with clinically uncertain Parkinsonian syndrome. Its diag- nostic indication expanded for the differential diagnosis of probable dementia with Lewy bodies (DLB) from Alzheimer disease in July 2006 (19). In addition to Europe, Korea re- 123 cently approved 123I-FP-CIT for clinical use in 2011 (20). • I-FP-CIT (A) has faster More than 300,000 people in 34 countries have undergone 123I-FP-CIT brain123 SPECT as of 2011 (21). Table 1 shows the kine cs than approval year of severalI-β representative-CIT (B) DAT imaging radio- ligands for clinical use. In Europe, 123I-b-CIT is also avail- • Allows scanning 3-6 hours able for routine clinical use. Another radioligand for DAT imaging, 99mTc-TRODAT-1, was approved for routine clini- a er injec on cal use in Taiwan in 2005 but was reported to be underutil- ized for bureaucratic and economic reasons despite the advantageous imaging properties of technetium (22). Several DAT radioligands for PET have been developed. 18F-FP-CIT 123 is available18 for clinical use in Korea;99m its first approval any- • I-βwhere-CIT, in the worldF-FP-CIT, was by the Korean FDATc- in 2008 (23). A TRODAT-1 approved in some newer synthesis method published in 2007 contributed to the clinical use of 18F-FP-CIT by significantly improving the countries, not US) radiochemical yield (24). CHARACTERISTICS OF 123I-FP-CIT 123I-FP-CIT is a radioiodinated cocaine analog. The phys- ical half-life of 123I is 13 h, and the major g-ray from 123I 123 decay has an energy of 159 keV. 123I-FP-CIT is classified as FIGURE 1. Faster kinetics of I-FP-CIT. In human striatum, 123I-FP-CIT (A) is taken up more rapidly than 123I-b-CIT (B). a schedule II controlled substance under the Controlled Sub- Practical clinical advantage of fast kinetics of 123I-FP-CIT is that stances Act in the United States. Registration with the Drug patientsAmerican can be scanned Society on same day of 3– 6hafterinjection.Neuroimaging Laruelle et al (1994)Enforcement J Cereb Agency Blood is required Flow to Metab order it, 14: and appropriate982-994 (Panel B reprinted with38 permissionth Annual of Meeting (26).)
123I-FP-CIT DAT IMAGING • Park 223 WHAT IS THE CLINICAL NEED? Diagnosis
• Parkinson disease (PD) symptoms/signs may overlap with other neurodegenera ve disorders especially in early disease • Demen a with Lewy Bodies is commonly misdiagnosed as Alzheimer’ disease • Misdiagnosis is common – clinicopathological study (n=100 clinically diagnosed PD cases) only 90/100 sa sfied neuropathological criteria for PD – misdiagnosis →∼5–25% receive inappropriate treatment – ~ 20% not diagnosed despite medical evalua on • QOL will likely decline if inappropriately treated
Suchowersky et al. Practice Parameter: Neurology American Society of Neuroimaging 2006; 66: 968-976. 38th Annual Meeting
Suchowersky Oet al. Practice Parameter: Diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66: 968-976. IMAGING DOPAMINERGIC DEGENERATION IN THE CLINIC
• Striatal dopamine transporter density is reduced in condi ons with substan a nigra degenera on, such as: • Parkinson’s disease • typically asymmetric loss of signal, putamen > caudate • Demen a with Lewy bodies
Le panel: pa erns of reduc on of i123I-FP-CIT uptake Right panel: (A) Healthy volunteer; (B) Parkinson’s disease; (C) Alzheimer’s disease, (D) Demen a with Lewy bodies
Catafau et al (2004) Mov Disord 19:1175-1182 American Society of Neuroimaging 38th Annual Meeting Walter et al (2002) J Neurol Neurosurg Psych 73: 134-40 DAT IN PARKINSON’S DISEASE VS ESSENTIAL TREMOR
American Society of Neuroimaging Cummings et al (2011) Brain:134-3146-3166 38th Annual Meeting 123I-FP-CIT SPECT IMAGING AND DIAGNOSIS
A. Healthy volunteer B. Dopa-responsive dystonia
FIGURE 3. Superior spatial resolution of brain 18F-FP-CIT PET images. Superior C. Juvenile parkinsonism spatial resolution of brain PET enables us to see caudate nucleus and putamen separately, and to analyze small brain structures such as in brain stem area. Another advantage of 18F-FP-CIT PET is that it can be acquired 2–3 h after injection.
trial is problematic (33). DAT imaging is not necessary in in the subcortical white matter (42). In vascular parkinson- clinically definite PD patients. DAT imaging is currently ism, DAT imaging shows normal or near-normal results, not recommended as a stand-alone diagnostic tool (33). It unless there is focal basal ganglia infarction, which leads O’Sullivan et al (2001) Neurology:56-266-267 does not help to differentiate PD from atypical Parkinso- to the characteristic punched-out deficit (13). DAT imaging nian syndrome (APS) (e.g., multiple-system atrophy, pro- gressive supranuclear palsy). Both PD and APS have presynaptic dopaminergic degeneration and demonstrate decreased striatal uptake on DAT imaging. Postsynaptic dopaminergic imaging needs to be added to increase diag- nostic accuracy (35). Postsynaptic D2 receptor binding is normal or increased in PD whereas it is decreased in APS Healthy volunteers versus 18 (36). F-FDG PET has been also used to distinguish PD from APS using their different metabolic patterns (37–39). Whether DAT imaging is useful in the assessment of treatment re- parkinsonism sponse, monitoring of disease progression, and early diagnosis of PD in the premotor stage is still in its research phase.
DIFFERENTIAL DIAGNOSIS OF PARKINSONISM Diagnostic possibilities in parkinsonism or tremor in- Group I: symmetric parkinsonism, clude a variety of diseases (Fig. 4). DIP, which is induced by dopamine receptor antagonist drugs, and essential tremor, which has characteristic kinetic or postural tremor, are 2 of the most common diagnostic errors (40,41). They orobuccal dyskinesias show normal DAT imaging results, which make it easy to differentiate them from PD (Fig. 5). Parkinsonism can also come from a cerebral infarct. Vascular parkinsonism may Group II: asymmetric parkinsonism occur when there are vascular lesions in the basal ganglia or
FIGURE 5. Differential diagnosis of parkinsonism using brain 18F-FP-CIT PET. Brain PET/CT images of 18F-FP-CIT uptake at level of striatum demonstrate different DAT density in different conditions. DAT density is decreased in PD patient (B), whereas DAT density is normal in healthy subject (A) and in patients with drug-induced parkinsonism (C) and essential tremor (D). DAT imaging is useful for differential diagnosis of various causes of parkinsonism. Clinical diagnosis of parkinsonism is quite often straightforward, obviating additional tests, but when overlap Tinazzi et al (2008) Mov Disord 23: 1825-1829 American Society of Neuroimagingand incomplete syndromes are present, improvements in FIGURE 4. Variety of diseases mimicking idiopathic PD. diagnostic accuracy may be possible using DAT imaging. Park (2012) J Nucl Med Technol 40: 222-228 38th Annual Meeting 123I-FP-CIT DAT IMAGING • Park 225 123I-FP-CIT-SPECT IN CLINICALLY UNCERTAIN CASES (I)
• Prospec ve, longitudinal study to compare clinical diagnosis baseline vs 123I-FP-CIT SPECT measured against 3 year clinical diagnosis • Primary efficacy popula on = 102 pa ents with diagnos c uncertainty (neurodegenera ve Parkinsonism or non-neurodegenera ve tremor disorder)
• SPECT: • Sensi vity 78% (95% CI: 66.0, 87.5); PPV: 98.2% (95% CI: 90.1, 100) • Specificity 97% (95% CI: 8383, 99.9); NPV: 66.2% (95%CI: 49.8, 80.0) • Baseline clinical diagnosis: • Sensi vity: 93% (95% CI: 84.3, 97.7) • Specificity: 47% (95% CI: 27.5, 66.1)
American Society of Neuroimaging Marshall VL et al (2009) Mov Disord 24: 500-508 38th Annual Meeting
Marshall VL et al (2009) Mov Disord 24: 500
123I-FP-CIT-SPECT IN CLINICALLY UNCERTAIN CASES (II)
• Retrospec ve chart review of 65 pa ents with cliically uncertain parkinsonian syndromes who underwent 123I-FP-CIT-SPECT (DaTSCAN) in a ter ary referral center
• Management changed in 63% • Confidence in diagnos c accuracy increased • Concluded that scan had a significant impact upon clinical management
American Society of Neuroimaging Sadasivan and Friedman (2015) Parkinsonism 38th Annual Meeting Relat Disord 21: 42-5
Marshall VL et al (2009) Mov Disord 24: 500
123I-FP-CIT-SPECT IN VASCULAR AND DRUG-INDUCED PARKINSONISM • Meta-analysis of 5 studies in pa ents who underwent 123I-FP- CIT-SPECT (DaTSCAN)
! sensitivity! specificity! positive! negative! likelihood!ration! likelihood!ratio! PD!v!VP! 86.2%!! 82.9%! 4.813!! 0.190!! (81.3?90.1)! (67.9?92.8%)! (1.523?15.211)! (0.139?0.259)! PD!v!DIP! 86.2%!! 93.8%!! 5.366!! 0.178!! (81.3?90.1)! (69.8?99.8%)! (1.913?15.050)! (0.125?0.253)! ! ! PD:!Parkinson’s!disease;!VP:!vascular!parkinsonism;!DIP:!drug?induced! parkinsonism.!! Parentheses!mark!95%!confidence!intervals!
American Society of Neuroimaging Brigo et al (2014) Eur J Neurol 21: 1369-e90. 38th Annual Meeting WHAT IS THE RESEARCH NEED? Overcome roadblocks to drug development
• Tracking progression and measuring response to interven on • Measures of disease progression almost exclusively rely upon the UPDRS • Depends upon symptoma c benefit
• Iden fica on of pre-motor disease • Would allow tes ng strategies for disease preven on
American Society of Neuroimaging 38th Annual Meeting DIAGNOSTIC UTILITY IN CLINICAL TRIALS
• SWEDDs: Scans without evidence of dopaminergic deficit false nega ves versus misdiagnosis
• Misdiagnosis in at least some cases is supported by: • Long term follow up1 • Transcranial sonography2 • Gait analysis3 • Electrophysiological studies4 1. Seibyl J et al (2005) Minerva Med 96: 353.; 2. Stockner H et al (2012) Mov Disord 27: 1182; 3. Mian OS et al (2011) Mov • Some of these study Disord 26: 1266; 4. Schwingenschuh D et al (2010) Mov Disord par cipants may have adult- 25: 560; 5. Schneider SA et al (2007) Mov Disord 22: 2210 onset dystonic tremor5
American Society of Neuroimaging 38th Annual Meeting QUANTITATION AND NIGROSTIATAL CELL LOSS
Figure 1. Resolution: standard / high Figure 2. Resolution: standard / high
Unilateral 6-OHDA-induced changes in [123I]β-CIT SPECT/CT and immunohistochemical findings. All results are presented as percentage of the lesioned/left side versus the intact/right side. (A) The 6-OHDA Representative pictures of striatal binding of [123I]β-CIT and immunohistochemical staining with injections caused a significant decrease in striatal [123I]β-CIT uptake as compared to intact rats at both 2 and 4 weeks post-lesion. Furthermore, the two different lesions (8 and 2 × 10 µg) could be distinguished with [123I]β- dopaminergic markers. Striatal activity of [123I]β-CIT detected with SPECT/CT (coronal view (A) and CIT SPECT/CT. Intrastriatal injection of 8 or 2 × 10 µg 6-OHDA resulted in extensive loss of (B) DAT- and (C) TH-immunoreactive fibers in the striatum, but there was no significant difference between the two lesion transversal view (B)), DAT immunoreactivity in the striatum (C), TH immunoreactivity in the striatum (D), and groups. However, when counting (D) TH-reactive cells in the substantia nigra pars compacta, the cell loss nigral TH-immunoreactive cells (E) in intact and 6-OHDA-lesioned rats (8 and 2 × 10 µg 6-OHDA) at 4 weeks significantly differed between the lesion types. All results are shown as mean ± SEM. ***P < 0.001 as compared to intact rats; #P < 0.05, ##P < 0.01, and ###P < 0.001 as compared to 8-µg 6-OHDA lesion group (one-way post-lesion. The orientation of the pictures is denoted in (A) with left (L) and right (R). Scale bar in (E) is 500 ANOVA followed by Tukey post hoc test, n = 4 to 5 per group). Bäck et al. EJNMMI Research 2013 3:46 doi:10.1186/2191-219X-3-46 Download authors' original image American Society of Neuroimaging Bäck et al (2013) EJNMMI Research 3:46 38th Annual Meeting TRACKING DISEASE PROGRESSION: CALM-PD
Parkinson’s Study Group (2002) JAMA 287: 1653 American Society of Neuroimaging 38th Annual Meeting DAT VERSUS OTHER DOPAMINE NEURON MARKERS
(A–C) Individual PET measurements (n = 78) are joined by straight line. Longitudinal decline in Fi ed regression curves: colored lines binding/uptake in the more Blue: [11C](±)dihydrotetrabenazine (DTBZ); affected putamen in subjects comple ng all Green: 6-[18F]fluoro-l-DOPA (FD) visits, n = 19. Red:(C) [11C]d-threo-methylphenidate (MP)
American Society of Neuroimaging Nandhagopal et al (2011) Brain 134: 3290-3298 38th Annual Meeting DAT IMAGING ASSOCIATION WITH CLINICAL PROGNOSIS
• Prospec ve study of de novo Parkinson’s disease pa ents • 123I-β-CIT SPECT at baseline • followed for 5.5 years/mean dura on of diagnosis of 6.3
Lower striatal binding associated with higher risk for: - motor-related disability, falling and postural instability - cogni ve impairment, psychosis
• Bo om vs top quar le for striatal binding • odds ra o = 3.3 for cogni ve impairment • odds ra o = 12.9 for psychosis
American Society of Neuroimaging Ravina et al (2012) Mov Disord 27:1392-7 38th Annual Meeting DAT AND MOVEMENT DISORDERS CONCLUSIONS • DAT imaging affords examina on of a fundamental biological process in many neurodegenera ve diseases • DAT imaging, using 123I-beta-CIT, 123I-FP-CIT, 18F-FP-CIT, and 99mTc-TRODAT-1, is approved and in use for diagnos c work up of parkinsonism in many countries • 123I-FP-CIT is the first available biomarker in the US to aid diagnos c work up of parkinsonism • Poten al clinical use for prognosis and progression needs to be defined
• Recogni on of SWEDDs in clinical trials may allow more precise enrollment • Longitudinal changes hold hope as a biomarker of nigrostriatal degenera on American Society of Neuroimaging 38th Annual Meeting LIMITATIONS
• What parameters for use as a diagnostic and screening tool?
• Tracking progression • Requires robust reliability and highly accurate quantitation • DAT expression and/or quantitation may be confounded by compensatory mechanisms, dopaminergic medications, other medications commonly prescribed for non-motor symptoms
• Testing for neuroprotection • Any neuroprotective approach would likely have a small effect only on rate of signal loss
• Only images one system • Multimodal approach more desirable?
• Accessibility, standardization and cost American Society of Neuroimaging Perlmutter and Norris (2014) Ann Neurol 76: 769-83 38th Annual Meeting OVERCOMING LIMITATIONS WITH OTHER IMAGING MODALITIES
• PIB for in vivo amyloid imaging in PD dementia • Variable pathology includes amyloid deposition or cortical Lewy bodies or neither
Burack et al (2010) Neurology 74: 77-84 American Society of Neuroimaging Donaghy et al (2015) Am J Geriatr Psychiatry 23: 23-37 38th Annual Meeting
ACKNOWLEDGEMENTS
Funding Biogen Dana Foundation Michael J Fox Foundation NINDS Special thanks to all our research Parkinson’s Disease Foundation participants Solomon Family Foundation Starr Foundation
Weill Cornell Medical Center-New York NY M. Flint Beal MD James Carter Natalie Hellmers Xiangling Mao MS P. David Mozely MD Bill Nikolov MD Mattson Ogg Dikoma C. Shungu PhD Tom Tropea MD Nora Weiduschat MD
American Society of Neuroimaging 38th Annual Meeting