SPECT Imaging of Dopamine Transporters With ^99mTc-TRODAT-1 in Major Depression and Parkinson's Disease

SPECT dopamine transporter imaging of the brain showed high-density radioactive uptake in corpora striatum, and moderate distribution in brain stem and certain regions of frontal lobe, but little in the occipital lobe and cerebellum. Notably, the dopamine transporter imaging in corpora striatum was different among the healthy-comparison, MDD, and PD groups. SPECT brain imaging indicated that the specific uptake of ^99mTc-TRODAT-1 binding was significantly higher in the basal ganglia of brain. There was no significant ^99mTc-TRODAT-1 binding in the other areas of the brain in healthy-comparison, MDD, or PD groups. In the healthy-comparison group, most cases showed symmetric, well-defined and even ^99mTc-TRODAT-1 radio signals of striata (Figure 1; panel A), whereas in the majority of MDD patients, the signals were reduced, and the outlines of radioactive striatum structures were not well defined (Figure 1; panel B). In PD patients, the radio signals were further reduced, and the full striatum structure was rarely seen (Figure 1; panel C). Only isolated radio dots were seen in the area of striata.

There was no significant difference in the ^99mTc-TRODAT-1 signals between the two hemispheres in any of the three groups, so that the right striatum/left striatum ratios were close to 1 in all groups (Table 2). However, when the ^99mTc-TRODAT-1 signals were normalized by those in the internal reference cerebellum, we found that both the right striatum/cerebellum and left striatum/cerebellum ratios were significantly decreased in MDD and PD, relative to comparison subjects (Table 2). This decrease was more severe in PD than in MDD. These results suggest that dopamine transporter is deficient in the striatum of patients with MDD, but this deficiency is not as severe as in the brains of patients with PD.

Dopamine transporter is a glycoprotein localized in the presynaptic membrane of the dopaminergic neuron, and it plays a key role in maintaining normal brain function, including movement, emotion, and other higher-level cognitive functions. The major function of the dopamine transporter is to take dopamine from the synaptic cleft back to dopaminergic neurons and thereby regulate dopamine level in the synaptic cleft. Dopamine transporter imaging is an important indicator in diagnosing PD.⁸ At present, ^99mTc-TRODAT-1, an agent with high affinity to dopamine transporter, has been used as a brain-imaging agent for assisting in the diagnosis of PD.^8–11 Several recent studies have documented monoamine loss for multiple monoamines, excessive clearance of monoamines through greater monoamine transporter binding, and excessive metabolism of monoamines in MDD.¹² These observations have led to a monoamine hypothesis of major depressive disorder.

To our knowledge, the present study is the first to compare specific nigrostriatal dopamine system deficits between major depressive disorder and Parkinson's disease. We used the cerebellum as an internal reference and found that the radioactive ^99mTc-TRODAT-1 uptake in the striatum over cerebellum (striatum/cerebellum) was markedly decreased in both MDD and PD, relative to age-matched, healthy-comparison subjects. An outstanding feature of the present study is that none of patients had received any treatments with dopaminergic, antidepressants, or antipsychotic drugs within 2 years. The absence of medical treatment for depression and psychomotor symptoms was not uncommon for people age 50 years and older in some areas of China, because it was thought that these symptoms are part of the normal aging process, given the lack of knowledge of mental health issues. This feature of our subjects eliminated any possible effects of the treatments on technetium-99m-TRODAT-1 SPECT imaging. Our findings support the idea of hypofunction of dopamine transporter in the striatum in PD and MDD, and are consistent with findings of previous studies.^12,13

Laine et al.¹⁴ investigated the relationship between depressive symptoms during alcohol withdrawal and decrease of dopamine transporter availability by using β-CIT SPET. They found a significant correlation between dopamine transporter and depressive symptom scores during withdrawal and after sobriety. The findings suggest a possible role of dopaminergic neurotransmission in depression. In the present study, we found that the radioactivity right striatum/cerebellum and left striatum/cerebellum ratios in MDD patients were significantly lower than those in healthy subjects, although they were not as low as in PD patients. However, the lower dopamine transporter signal in the PD group relative to the MDD group might also be attributed to the longer disease duration (7 months) of Parkinson's disease than major depressive disorder. Leenders¹⁵ reported that the estimated annual striatal dopaminergical neuronal loss in PD patients is 6%–11% per year, as assessed with dopamine transporter tracers, whereas the average annual loss in healthy-comparison subjects is about 0.8%.¹⁶ Remy et al.¹⁷ found no difference in carbon-11-RTI-32 uptake in the striatum or the substantia nigra between Parkinson's disease patients with and without depression. It appears that the presence of Parkinson's disease is more likely to influence the results than the disease duration.

In this study, we found that the dopamine transporter of the basal ganglia region in patients with major depressive disorder was decreased, supporting the dopamine-lesion model of major depressive disorder. Several studies on dopamine transporter imaging in major depressive disorder have been previously reported, but the results did not reach consensus. Some studies indicated that the dopamine transporter of basal ganglia region in patients with major depressive disorder was decreased,¹⁸ but other studies showed normal levels both before and after treatment¹⁹ or even demonstrated that the dopamine transporter of basal ganglia region in patients with major depressive disorder was increased.^20,21 In the present study, the patients had been ill for 7 months, and the eligibility criterion was a score of at least 24 on the 17-item Ham-D, plus psychomotor retardation. This suggests that the patients included in the present study had a longer interval between the onset of disease and the first clinical visit and were more severe in symptoms. Furthermore, various endogenous dopamine levels under different conditions could also affect the number of receptors available, reducing the radio ligand uptake in these studies.

Tzen et al.¹¹ studied dopamine transporter levels in the striatum and putamen by ^99mTc-TRODAT-1 and reported that dopamine transporter level at the side opposite to the diseased limb is decreased in PD patients. We did not find any significant difference in dopamine transporter uptake between the two hemispheres of the brain in PD patients. The discrepancy between our study and Tzen et al.'s may be the result of the research subjects included in the two studies. We also found that there was no difference in dopamine transporter signals between the two hemispheres in major depressive disorder, suggesting doparminergic hypofunction in the striatum of both sides of the brain.

In conclusion, we demonstrated a deficient dopamine transporter in the striatum in major depressive disorder. These results support the hypothesis of dopamine hypofunction in major depressive disorder and suggest that deficient dopamine transporter may be involved in the mechanism of severe major depressive disorder.

Studies described in this report were supported by grants from the Zhejiang Health Science Research Foundation (2005B094) and the Zhejiang Science and Technology Project (2008C33041).