CONTRAST AGENT EVALUATION [123I]FP-CIT SPECT in atypical degenerative parkinsonism One of the most widely used techniques to support the clinical diagnosis of Parkinson’s disease is the SPECT scan with [123I]FP-CIT. This tracer binds reversibly and visualizes the striatal presynaptic dopamine transporters. Several uncertainties remain on the value of [123I]FP-CIT and SPECT in atypical degenerative parkinsonian syndromes. In this concise review, we discuss the contribution of SPECT and [123I]FP-CIT in supporting the clinical diagnosis of Parkinson’s disease and their role in the differential diagnosis of Parkinson’s disease and atypical degenerative parkinsonism. The chemistry, pharmacodynamics and pharmacokinetics of [123I]FP-CIT are also discussed. 1,2,3 KEywordS: atypical degenerative parkinsonism n FP-CIT n ioflupane n SPECT Ioannis U Isaias* , Giorgio Marotta4, Gianni Pezzoli2, Parkinson’s disease (PD) is the second most dystonic tremor [15] and psychogenic parkin- Osama Sabri5 [1] [16,17] 5,6 common neurodegenerative disorder , yet sonism . In this concise review, we will & Swen Hesse 123 early accurate diagnosis remains challenging. discuss the role of SPECT and [ I]FP-CIT in 1Università degli Studi di Milano, The estimated prevalence of PD is 0.5–1% in supporting the clinical diagnosis of PD and its Dipartimento di Fisiologia Umana, those aged 65–69 years and 1–3% in those aged differential diagnosis with ADP. Milano, Italy 2Centro per la Malattia di Parkinson e i ≥80 years [1]. Although the clinical diagnosis of Disturbi del Movimento, Istituti Clinici PD may be straightforward in cases with a classic [123I]FP-CIT SPECT scans in atypical di Perfezionamento, Milano I-2016, Italy presentation [2], accurate distinction between PD degenerative parkinsonism 3Universitätsklinik Würzburg, and atypical degenerative parkinsonism (ADP) Clinically, MSA is a sporadic, progressive neuro- Neurologische Klinik und Poliklinik, Würzburg, Germany may be difficult, particularly in the early or mild degenerative disease characterized by varying 4Dipartimento di Medicina Nucleare, stages of disease [3]. In autopsy series, ADP (mul- severity of parkinsonian features, cerebellar Fondazione IRCCS Ca’ Granda tiple system atrophy [MSA], progressive supra- ataxia, autonomic failure and corticospinal Ospedale Maggiore Policlinico, Milano, Italy nuclear palsy [PSP] and corticobasal syndrome disorders [18]. 5Department of Nuclear Medicine, [CBS]) accounted for half of PD misdiagnoses at PSP presents with early onset postural insta- University of Leipzig, Germany 6IFB Adiposity Diseases, Leipzig specialized centers [4,5], while in the community bility associated with supranuclear vertical gaze University Medical Centre, Leipzig, Alzheimer’s disease and vascular parkinsonism impairment, symmetrical akinetic-rigid syndrome Germany *Author for correspondence: were most common [6,7]. Assessment of the clini- together with prominent bulbar dysfunction, [email protected] cal features suggests that an accuracy of 90% dementia and axial rigidity [19,20]. for PD may be the highest that can be expected CBS is characterized by asymmetric akinetic- using the currently available clinical diagnos- rigid parkinsonism and limb dystonia, variably tic criteria. Accurate diagnosis of patients with associated with cortical signs [21]. ADP is important to predict the disease course The parkinsonian types of MSA (MSA-P) and and avoid unnecessary medical examinations PSP (PSP-P) can be very difficult to distinguish and therapies and their associated side effects, from PD before disease-specific signs and symp- safety risks and financial costs. Correct diagno- toms occur. This also applies to CBS because sis is also critically important when patients are of its marked asymmetrical akinetic-rigid syn- being recruited into clinical trials. drome before apraxia, myoclonus and cognitive Post-mortem studies demonstrate severe problems become evident. Correct differentia- reductions in dopamine concentration in the tion is important as PD has a better prognosis striatum of patients with PD, with greater than ADP syndromes and responds better to a reductions in the putamen [8,9]. SPECT with symptomatic treatment [22]. [123I]FP-CIT specifically identifies presynap- In PD the decrease in [123I]FP-CIT binding tic dopaminergic deficits within the striatum usually occurs in the dorsal putamen contralat- [10–13]. Accordingly, an abnormal dopamine eral to the side of the neurological symptoms, transporter SPECT image should be regarded in time progressing anteriorly and ipsilaterally as exclusion criteria for essential tremor [14], (Figure 1) [12,14,23]. part of 10.2217/IIM.12.21 © 2012 Future Medicine Ltd Imaging Med. (2012) 4(4), 411–421 ISSN 1755-5191 411 CONTRAST AGENT EVALUATION Isaias, Marotta, Pezzoli, Sabri & Hesse Figure 1. [123I]FP-CIT of healthy controls and Parkinson’s disease subjects. [123I]FP-CIT SPECT images and binding values of healthy subjects and patients with Parkinson’s disease or atypical degenerative parkinsonism. Several studies investigated PD and ADP [123I]b-CIT uptake was found in patients with by means of [123I]FP-CIT and SPECT scans. MSA-P and allowed a correct classification of However, only few specifically established the 95% of MSA-P and PD patients [23,30]. Finally, value of [123I]FP-CIT in setting a differential clinically pure forms of MSA-C (cerebellar diagnosis (Table 1). variant) may show a DAT binding loss but less The amount and pattern of reduced striatal compared with MSA-P or PD [31]. DAT binding in MSA have been demonstrated Antonini and colleagues reported a greater to be within the range of PD. However, asym- DAT reduction in patients with PSP (0.51 ± 0.39; metry of DAT binding loss tends to be more p < 0.01) compared with MSA-P patients pronounced in PD and the progression of (0.70 ± 0.33) or PD patients (0.95 ± 0.38) [32]. dopaminergic innervation loss is faster in MSA No difference was found between patients with compared with PD [24,25]. In a recent study that MSA and PD. Putamen/caudate ratios were compares the accuracy of dual-tracer DAT and greater in PSP (0.83 ± 0.12; p < 0.01) than in perfusion SPECT imaging in the differential PD patients (0.51 ± 0.11), suggesting a more- diagnosis of parkinsonism using template-based uniform involvement of dopamine nerve ter- discriminant ana lysis [26], no reduction of MSA minals in both caudate nucleus and putamen. versus PD was noted. In contrast to what was Van Laere and colleagues also demonstrated a reported by Scherfler and colleagues, demon- greater involvement of the caudate heads in PSP strating differential [123I]b-CIT binding capac- patients, although when directly contrasted with ity between PD and MSA [27], the aforemen- PD patients, a difference was found in the left tioned study could not detect differences even striatum only at a p = 0.05 uncorrected level [26]. at the least stringent threshold (p = 0.05 uncor- DAT loss in CBS is in the same range as that rected). The reverse contrast (PD < MSA) in PD patients [33–35]; but more asymmetrical and demonstrated a decreased binding in the left less pronounced than in MSA and PSP patients posterior putamen. However, El Fakhry and [34]. In CBS, unlike PSP or PD, unilateral bal- colleagues reported lower striatal binding val- anced (caudate/putamen) reduction in tracer ues in PD (55%) and MSA (23%) compared uptake has been observed [33]. DAT binding may with normal controls (p < 0.01) and lower val- result occasionally within the normal range in ues in PD compared with MSA (p < 0.05) [28]. patients with CBS [35–37]. The low sensitivity and Asymmetry index was greater for PD than for specificity of 123[ I]FP-CIT for the diagnosis of MSA and controls in both the caudate nucleus CBS also relies on the pathological and clinical and the putamen (p < 0.05). In addition, there heterogeneity of this syndrome (Figure 2) [37,38] . was a significantly decreased perfusion in the left Overall, a meta-ana lysis of diagnostic accu- and right nucleus lentiformis in MSA compared racy on SPECT in parkinsonian syndromes with PD and controls (p < 0.05). [39] revealed, for presynaptic tracers in gen- A reduction of [123I]b-CIT uptake in the mid- eral, a moderate to high sensitivity but a low brain appears to separate patients with clinically specificity in differentiating PD from MSA and fully developed MSA-P or PSP from patients PSP (pooled odds ratio with 95% CI was 2). with PD [23,27,29]. Indeed, a reduced midbrain Similarly, presynaptic tracers showed a very 412 Imaging Med. (2012) 4(4) future science group [123I]FP-CIT SPECT in atypical degenerative parkinsonism CONTRAST AGENT EVALUATION high sensitivity (78–100%) but a low specific- clinical diagnosis can be obtained. On the other ity (0–33%) in discriminating between MSA hand, a normal result is considered inconsistent and PSP (pooled odds ratio with 95% CI was 2). with a clinical diagnosis of PD or ADP [39,40]. In conclusion, [123I]FP-CIT and SPECT have Postsynaptic dopamine receptor imaging, in little value in discriminating between ADPs in addition to presynaptic dopamine transporter routine clinical practice and they should be imaging, may be necessary, together with clinical used with great care when differentiating ADP reassessment and follow-up imaging, to improve from PD, as only hints towards a more accurate diagnostic accuracy in PD and ADP [41]. The Table 1. Summary of [123I]FP-CIT findings in subjects with atypical degenerative parkinsonism. Study (year) Tracer Clinical diagnosis Imaging findings ref. Benamer et al. [123I]FP-CIT PD (n = 145), MSA (n = 2), Clear visual differentiation between ET and HC vs PD and [10] (2000) PSP (n = 10), ET (n = 33), atypical parkinsonism. No differences between atypical HC (n = 38) parkinsonism and PD Antonini et al. [123I]FP-CIT PD (n = 70), MSA (n = 10), Striatal binding reduced in PD, MSA and PSP vs HC [32] (2003) PSP (n = 10), HC (n = 12) Greater and more uniform bilateral binding loss in PSP vs PD and MSA Plotkin et al.