[sup 123 I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease

Parkinson's disease (PD) develops insidiously with a prolonged presymptomatic phase during which mesencephalic dopaminergic neuronal loss occurs. ^[1-5] The clinical presentation of PD characteristically begins with unilateral symptoms that gradually, but relentlessly, progress to involve both sides. ^[6,7] Patients identified very early in the course of their disease with only hemiparkinsonism help to establish the threshold of early clinical detection of PD. Furthermore, by contrasting the symptomatic with the presymptomatic side, these patients provide a natural model in which to evaluate methods for presymptomatic detection of PD. For example, studies examining motor function in hemi-PD patients, by using electrophysiologic assessments, have demonstrated motor abnormalities in the presymptomatic and the symptomatic side. ^[8] PET studies have shown a reduction in [sup 18 F]fluorodopa ([sup 18 F]FDopa) uptake in early hemi-PD patients in the striatum ipsilateral and contralateral to symptoms. ^[9-11] In addition, PET studies have identified a dopaminergic deficit before symptoms in subsets of individuals at risk for PD or other parkinsonian syndromes. ^[12-15]

In vivo single-photon emission computed tomography (SPECT) and PET imaging of the dopamine transporter provides an alternative approach to examine the mesencephalic dopamine neuronal projections in early PD. The dopamine transporter is a protein located in the presynaptic membrane on the terminals of dopaminergic projections from the substantia nigra to the striatum and provides a marker of dopamine terminal innervation. ^[16] Prior studies have demonstrated that striatal uptake of [sup 11 C]nomifensine, a monoamine transporter inhibitor, was reduced comparably with [sup 18 F]FDopa uptake in patients with PD. ^[17] Several phenyltropane analogues of cocaine, including 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([sup 123 I] beta-CIT) and [sup 11 C]CFT, have been developed as PET and SPECT probes of the dopamine transporter with high affinity and low nonspecific binding. ^[18-20] Initial clinical studies using these probes have demonstrated significant striatal dopamine transporter loss in patients with PD. ^[21-23] More detailed SPECT imaging studies have shown that the reduction in [sup 123 I] beta-CIT striatal uptake in PD patients correlates with severity of disease and that the reduction in [sup 123 I] beta-CIT striatal uptake is greater in putamen than in caudate. ^[23,24] In this study, we compared SPECT imaging with [sup 123 I] beta-CIT in eight early-PD patients with hemiparkinsonism exclusively and eight age- and sex-matched healthy subjects. Our goals were to examine the extent of transporter loss in patients with minimal symptoms and to determine whether SPECT imaging with [sup 123 I] beta-CIT can identify striatal dopamine transporter loss in hemiparkinsonism in the striatum contralateral to symptoms (the symptomatic side) and the striatum ipsilateral to symptoms (the presymptomatic side).

Methods.

Results.

The patients in this study had mild, exclusively hemi-PD with total UPDRS of 21.6 +/- 3.4 (all data expressed as mean +/- SEM) and a mean disease duration of 1.4 years. Five of the eight patients were newly diagnosed and three had been followed for up to 4 years. One patient was treated with pergolide and two patients with selegiline. In vitro studies have demonstrated weak inhibitory effects of L-selegiline on the selective dopamine transporter inhibitor [sup 3 H]GBR-12935 binding in rat striatal slices. ^[31] All patients were L-dopa naive to minimize drug effect on imaging results.

[sup 123 I] beta-CIT brain activity was highly concentrated in the striatal region (Figure 1). In the hemi-PD patients, striatal [sup 123 I] beta-CIT activity was reduced bilaterally, although the reduction in activity was greater contralateral to the symptomatic side. Both measures of [sup 123 I] beta-CIT uptake, total striatal uptake expressed as percent injected dose (AI = 25.3 +/- 3.5) and the ratio of specific to nondisplaceable striatal uptake (AI = 30.0 +/- 3.9), demonstrated an asymmetric loss of transporter activity, which in each patient was greater contralateral to the symptomatic side (Figure 2). In contrast, the healthy subjects showed no significant asymmetry, ie, total striatal uptake (AI = 4.3 +/- 1.2) and specific to nondisplaceable ratio (AI = 3.4 +/- 1.2). Comparison of the AI in the PD patients and healthy subjects was significant at p < 0.01 for both outcome measures.

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Figure 1. Single-photon emission computed tomography (SPECT) [sup 123 I] beta-CIT images from a healthy subject and from a patient with hemi-Parkinson's disease acquired 24 hours after injection. Note the asymmetric reduction in activity more marked in the putamen than caudate in the patient. Levels of SPECT activity are color encoded from low (black) to high (yellow/white).

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Figure 2. 2 beta-Carboxymethoxy-3 beta-(4-iodophenyl)tropane [sup 123 I] beta-CIT striatal uptake in eight hemi-Parkinson's disease/healthy subject pairs (mean age of pair indicated). For each pair, the ratio of the specific to nondisplaceable striatal uptake is compared in right and left striatum in the healthy subjects with striatum ipsilateral to symptoms (Ipsi) and contralateral to symptoms (Contra) in the hemi-Parkinson's disease patients. (open square = right; open square = left; ???? = ipsi; fill square = contra.)

The specific to nondisplaceable striatal uptake of the hemi-PD patients was reduced by 53 +/- 4% contralateral and by 37 +/- 5% ipsilateral to the symptomatic side compared with the mean uptake in age- and sex-matched healthy subjects (p < 0.01) (Figure 2). Similarly, the total striatal uptake expressed as percent injected dose of the hemi-PD patients was reduced by 52 +/- 5% contralateral and by 39 +/- 7% ipsilateral to the asymptomatic side compared with the mean total striatal uptake in age- and sex-matched healthy subjects (p < 0.01). In addition, in the eight hemi-PD patients, the relative reduction in the specific/nondisplaceable striatal uptake and in the total striatal uptake was significantly different in the side contralateral compared with the side ipsilateral to symptoms (p < 0.01).

Recent evidence has shown that striatal [sup 123 I] beta-CIT activity is reduced by about 3 to 7% per decade in healthy subjects. ^[32,33] In Figure 2, specific to nondisplaceable striatal uptake in healthy subjects and in hemi-PD patients was reduced with increasing age, ie, healthy subjects, p < 0.05; ipsilateral PD, p < 0.05; contralateral PD, p < 0.09 (examined with linear regression analysis). However, the relative reduction of tracer uptake in the hemi-PD patients compared with their age-matched controls did not vary with age, but rather was a fairly constant percentage of the healthy subject value. This result suggests that symptom threshold is not entirely dependent on an absolute reduction in dopamine transporter density, but may depend on age-related compensatory mechanisms of the dopaminergic brain circuitry. ^[34-36]

Anatomic and biochemical pathology as well as PET imaging have demonstrated that the dopaminergic loss in PD is greater in the putamen than the caudate. ^{[9,11,17,37,38]} Data comparing the relative loss of [sup 123 I] beta-CIT putamenal and caudate striatal uptake in the hemi-PD patients show a reduction in the putamen and caudate both contralateral (58 +/- 4% and 41 +/- 6%) and ipsilateral (44 +/- 6% and 22 +/- 6%) to symptoms compared with the putamenal and caudate uptake in age- and sex-matched healthy subjects (p < 0.01 for each of the four values). The greater loss of [sup 123 I] beta-CIT activity in the putamen is further reflected in Figure 3. The caudate/putamen uptake is increased in the hemi-PD patients both ipsilateral (1.5 +/- 0.1) and contralateral (1.5 +/- 0.1) to symptoms compared with their matched control subjects (1.1 +/- 0.1), p < 0.01.

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Figure 3. The ratio of caudate to putamen specific to nondisplaceable 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([sup 123 I] beta-CIT) uptake is compared in right and left striatum of healthy subjects with striatum ipsilateral to symptoms (Ipsi) and contralateral to symptoms (Contra) in the hemi-Parkinson's disease patients. (open square = right; open square = left; ???? = ipsi; fill square = contra.)

Discussion.

[sup 123 I] beta-CIT SPECT imaging of the dopamine transporter reliably distinguished patients with mild, hemi-PD disease from healthy subjects. Furthermore, these data showed that there is a significant reduction in [sup 123 I] beta-CIT striatal uptake contralateral (symptomatic side) and ipsilateral (presymptomatic side) to the parkinsonian symptoms. The interval between the onset of disease and the onset of symptoms in PD is unknown, but evidence suggests that the usual presymptomatic period may be several years. ^{[1,2,5,39,40]} Although patients with hemi-PD are by definition not strictly presymptomatic, the interval between diagnosis and development of bilateral symptoms may be as long as several years. ^[6] Therefore, our data show clearly that dopamine transporter imaging can identify PD patients at the onset of symptoms, and further suggest that dopamine transporter imaging may be able to identify presymptomatic patients destined to develop PD.

We selected two different outcome measures (total striatal uptake and the ratio of specific to nondisplaceable striatal uptake) to compare [sup 123 I] beta-CIT activity in parkinsonian patients and healthy subjects. Both outcome measures demonstrated a significant reduction in [sup 123 I] beta-CIT activity in both the symptomatic and presymptomatic striatum. Total striatal uptake is both a straightforward concept and a robust signal, because biodistribution studies have shown that approximately 1% of the injected dose is taken up by the striatum. ^[32] However, total striatal uptake will be influenced by variations in peripheral clearance between subjects. Importantly, the almost identical reduction in [sup 123 I] beta-CIT binding in PD patients, as measured by either total striatal uptake or the specific to nondisplaceable ratio, indicates that the peripheral clearance does not vary significantly among subjects. The specific to nondisplaceable ratio is a measure of specific [sup 123 I] beta-CIT in the target brain region to a control region. This ratio may be the most practical clinical measure, because it requires neither calibration of the camera relative to injected dose nor any plasma measurements. In addition, the kinetics of [sup 123 I] beta-CIT indicate that after a single injection of the ligand in healthy subjects a rise in activity occurs on day 1, but very stable levels of striatal activity are present from 18 to 30 hours after injection, with an average decline of 0.3%/hr. ^[32] PD patients achieve a plateau of activity on day 1, as expected from a decreased number of target sites. ^[22] Therefore, during this "equilibrium" period, the specific to nondisplaceable ratio is linearly related to the density of dopamine transporter sites in the striatum (given the likely assumptions that affinity [1/Kd] and nonspecific distribution volume [V2] is equivalent among subjects). In clinical practice, this measurement might be done at any convenient time the day after an injection of [sup 123 I] beta-CIT, taking full advantage of the relative ease and the longer half-life radioligands available with SPECT imaging.

PET imaging, using both general measures of metabolism (glucose) and more-specific measures of dopamine function, [sup 18 F]Fdopa, have been used by several investigators to examine the in vivo neurochemistry of early PD. ^{[9,11,17,40,41]} [sup 18 F]Fdopa imaging shows an approximate 50 to 60% decrease in putamenal activity and a 20 to 25% decrease in caudate activity in patients with PD. ^[10,11,17] Our data in hemi-PD patients show a similar reduction in putamenal [sup 123 I] beta-CIT activity of 58% and 41%, and in caudate [sup 123 I] beta-CIT activity of 44% and 22%, contralateral and ipsilateral to symptoms, respectively. [sup 18 F]Fdopa imaging is dependent on dopamine turnover and therefore may be influenced by neuronal metabolism, whereas the dopamine transporter binding site imaged by [sup 123 I] beta-CIT is a more direct measure of presynaptic mesencephalic dopaminergic neuron pathology. Although both [sup 18 F]Fdopa and [sup 123 I] beta-CIT are sensitive markers of PD, they may measure different aspects of the developing dopaminergic deficit in these patients. In particular, the increase in dopamine turnover that occurs in early PD may confound the [sup 18 F]Fdopa studies, suggesting that transporter imaging may more accurately reflect early dopaminergic loss.

Although the reduction in dopamine transporter density in the entire striatum clearly distinguishes hemi-PD patients from healthy subjects, more detailed examination of the striatum demonstrating the greater loss of [sup 123 I] beta-CIT uptake in the putamen than caudate may increase the sensitivity of [sup 123 I] beta-CIT imaging for early PD detection. This anatomy of dopamine transporter SPECT imaging is consistent with the relatively selective loss of dopamine in the posterior putamen in idiopathic PD in pathological and PET studies. ^[9,11,38] Similarly, the characteristic unilateral presentation of PD is reflected in the dramatic asymmetry in the loss of dopamine transporter uptake. Elevation of the caudate/putamen ratio and marked asymmetry of [sup 123 I] beta-CIT activity may be useful in distinguishing idiopathic PD from atypical parkinsonian syndromes that show a more uniform and usually symmetric striatal loss of dopaminergic activity both involving the caudate and putamen. ^[42] Thus, SPECT imaging with [sup 123 I] beta-CIT is a potential diagnostic tool to identify patients with PD with early or presymptomatic disease and to distinguish patients with PD from those patients with other parkinsonian syndromes. Given the wide availability of SPECT technology, dopamine transporter imaging may also be used to monitor progression of disease and to assess the efficacy of putative neuroprotective agents for PD.

Acknowledgments

We gratefully acknowledge the nuclear medicine technologist support of E.O. Smith and G. Wisniewski, data analysis by L. Poutages-Torak and Q. Ramsby, radiochemistry technical help of M. Stratton, and provision of CIT precursor from John Neumeyer of Research Biochemicals International.