Differential patterns of dopamine transporter loss in the basal ganglia of progressive supranuclear palsy and Parkinson's disease: Analysis with [¹²³I]IPT single photon emission computed tomography

Abstract

We evaluated the patterns of dopamine transporter loss in the striatum of ten controls, twenty patients with Parkinson's disease (PD), and nine with progressive supranuclear palsy (PSP) using ¹²³I-IPT single photon emission tomography (SPECT). Four ROIs in the striatum correspond to the head of caudate nucleus (ROI 1), a transitional region between head of caudate and putamen (ROI 2), anterior putamen (ROI 3), and posterior putamen (ROI 4). A striatal ratio of specific to nondisplaceable uptake (V3″) was calculated normalizing the activity of the ROIs to that of occipital cortex. V3″ values were significantly reduced in all ROIs of PD and PSP patients, compared with controls (p = 0.001). V3″ value in ROI 2 was significantly lower in PSP group, compared with PD group (p = 0.02). The percent reductions of striatal uptake in ROI 1, ROI 2, ROI 3 and ROI 4 were 56%, 53%, 64% and 78% in PD patients, whereas 75%, 72%, 75% and 77% in PSP patients, respectively. The reduction patterns of uptake were significantly different between PD and PSP groups (p = 0.001). In PD patients, the percent reductions of ¹²³I-IPT uptake were significantly greater in ROI 3 and 4 compared with ROI 1 or 2, whereas those were similar in all ROIs of PSP patients. In addition, PD patients showed a significantly higher posterior putamen / caudate ratio of reduced ¹²³I-IPT uptake than the anterior putamen / caudate ratio (p = 0.005). Our results implicate that ¹²³I-IPT SPECT is a relatively simple and reliable technique that may be useful in differentiating PD from PSP.

Introduction

Parkinsonism is a neurological syndrome manifested by any combination of six cardinal features: tremor-at-rest, bradykinesia, rigidity, flexed posture, freezing and loss of postural reflexes. Parkinsonism can be divided into four major categories: primary parkinsonism (idiopathic Parkinson's disease: PD), secondary parkinsonian syndrome (SPS), parkinsonism-plus syndrome (PPS) and heredodegenerative disorders. In large autopsy series, PD accounts for 75% to 80% among cases with parkinsonism, while both PPS and SPS range around 20% to 25% [1], [2], [3].

Since PPS and SPS may show considerable overlap in their clinical and pathologic features with PD, the clinical diagnosis may be inaccurate. The incidence of inaccurate clinical diagnosis of PD ranged from 15% to 24% in autopsy series [2], [3], [4]. Progressive supranuclear palsy (PSP), also called Steele–Richardson–Olszewski syndrome, is one of the most common PPS [3]. However, PSP may be often misdiagnosed as PD until clinical symptoms and signs are fully expressed [5], [6]. Currently, there is no biologic marker for the diagnosis of PD or PSP. Structural brain imaging studies including MRI do not help in differential diagnosis between PD and PSP. Neuropathologic examination remains the gold standard for the definite diagnosis of both diseases.

Functional brain imaging, especially imaging for the dopaminergic activity, may be more useful than structural imaging in evaluation of parkinsonism. [¹⁸F]dopa positron emission tomography (PET) is the most frequently employed tool to evaluate the dopaminergic pathway. It has been used to evaluate in vivo human striatal l-dopa decarboxylase activity [7] and dopamine turnover rates [8]. However, [¹⁸F]dopa PET has some limitations. One of disadvantages is the complexity of the kinetics and metabolism of [¹⁸F]dopa [9]. In addition, l-dopa decarboxylase activity depends on the disease-associated modulation of enzyme kinetics as well as dopaminergic neuronal integrity.

Recently, imaging of dopamine transporter (DAT) with single photon emission computed tomography (SPECT) or PET has been used to evaluate the presynaptic dopaminergic degeneration. It is considered as a reliable study closely reflecting the integrity of the dopaminergic neurons in PD [10], [11], since the DAT is mainly located on the terminals of dopaminergic neurons. [¹¹C]WIN 35,428 PET imaging of DAT can demonstrate the loss of dopaminergic nerve terminals in the striatum of patients with PD [11]. However, PET is not easily available in clinical environment because of the high cost and need of cyclotron.

The less expensive and more widespread SPECT technique of DAT has also been used to evaluate parkinsonism using [¹²³I] labelled 2-β-carboxymethoxy-3-β-(4-iodophenyl) tropane (¹²³I-βCIT) [10], [12], [13], [14], [15], or N-(3-iodopropen-2-yl)-2β-carbomethoxy-3β-(4-chlorophenyl) tropane (¹²³I-IPT) [16], [17]. SPECT with ¹²³I-βCIT or ¹²³I-IPT provided very reliable information on the presynaptic dopaminergic integrity in PD [10], [12], [13], [14], [15], [16], [17].

¹²³I-βCIT has been more widely used for SPECT imaging of DAT than ¹²³I-IPT, and its uptake in the basal ganglia (BG) peaked at 14–24 h postinjection. This slow uptake may not be the optimal characteristics in clinical applications for the imaging studies. ¹²³I-IPT has shown much faster kinetics, and its uptake in the striatum peaked at 1–2 h postinjection.

¹²³I-IPT is a relatively new ligand for the DAT with a binding affinity (K_d) of 0.2 nM in vitro [18], [19]. In vitro binding data using ¹²³I-IPT has suggested that binding is highly specific for the DAT. Preclinical studies in nonhuman primates have shown preferential uptake in the BG with a target to background ratio of 22.8 at 3 h postinjection [20]. Dynamic SPECT scans in monkeys have shown that some indirectly acting dopaminergic drugs affect the uptake and elimination kinetics of IPT in the BG, whereas postsynaptic dopamine receptor antagonists do not. Displacement of the IPT uptake with monoamine transporters, mazindol, GBR-12909 and β-CIT (RTI-55) suggested that the binding is reversible [20]. No pharmacological effects of the no-carrier-added tracer were observed in animal studies. Mozley and colleagues have measured the radiation dosimetry of IPT in normal controls and have recommended injection of 7.5 mCi (280 MBq) of injection dose for the worst case in any organ and 13.5 mCi (500 MBq) for the critical organ by using the mean value [21]. Ichise and colleagues have developed a noninvasive method to estimate the receptor parameter k₃/k₄ in humans with ¹²³I-iodobenzofuran SPECT [22].

Recently ¹¹C-WIN 35,428 PET revealed that patients with PD had a more pronounced loss of DAT in the posterior putamen than those with PSP [11]. However, more widely used SPECT as a DAT imaging has never been used in the differential diagnosis between PD and PSP.

The purpose of this study was to evaluate the distribution pattern of DAT in the striatum of patients with PD and PSP using ¹²³I-IPT SPECT, and to determine the usefulness of this technique in the differential diagnosis between PD and PSP.