Lie-Hang Shen

Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinsons disease (PD) and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D2 receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders.

Study on the neuroprotective effect of fluoxetine against MDMA-induced neurotoxicity on the serotonin transporter in rat brain using micro-PET.

3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[(18)F]-fluorophenylthio) benzylamine (4-[(18)F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague-Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[(18)F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[(18)F]-ADAM sites was measured. Specific 4-[(18)F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55-75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30-50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40-75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[(18)F]-ADAM micro-PET.

Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression.

The serotonin transporter (SERT) is hypothesized to be an important component of the pathophysiology of major depression (MD). The aim of this study was to use [(123)I]ADAM single-photon emission computed tomography (SPECT) to explore whether SERT availability in four regions of the brain (striatum, thalamus, midbrain and pons) is different in patients with MD and healthy individuals. The effects of three genetic variants (rs25531, rs6354 and STin2) of the serotonin transporter gene (SLC6A4) on SERT availability were also investigated. This study included 40 MD patients and 12 controls. The mean specific uptake ratio (SUR) values in the thalamus differed significantly between MD patients and controls. Genetic variants of SLC6A4, age, gender, severity of depression, and smoking behavior did not influence SERT availability. SERT availability might be a useful biomarker of the development of MD; however, a larger sample size is needed to provide more concrete evidence.

Effects of interleukin-15 on neuronal differentiation of neural stem cells.

Interleukin-15 (IL-15) signaling has pleiotropic actions in many cell types during development and has been best studied in cells of immune system lineage, where IL-15 stimulates proliferation of cytotoxic T cells and induces maturation of natural killer cells. A few reports have indicated that IL-15 and the IL-15 receptor are expressed in central nervous system tissues and neuronal cell lines. Because this aspect of IL-15 action is poorly studied, we used cultured rat neural stem cells (NSCs) to study IL-15 signal transduction and activity. Primary cultures of rat NSCs in culture will form neurospheres and will differentiate into neuron, astrocyte, and oligodendrocyte progenitors under permissive conditions. We found by immunofluorescence that the IL-15Ralpha subunit of the IL-15 receptor was expressed in NSCs and differentiating neurons, but not astrocyte or oligodendrocyte progenitors. We also showed that IL-15 treatment reduced MAP-2 protein levels in neurons and could reduce neurite outgrowth in differentiating neurons but did not affect NSC proliferation, and cell proportions and viability of the corresponding lineage cells. In the presence of a STAT3 inhibitor, Stattic, IL-15 no longer reduced MAP-2 protein levels. IL-15 treatment caused STAT3 phosphorylation. Furthermore, using anti-IL-15Ralpha antibody to block IL-15 signaling completely inhibited IL-15-induced phosphorylation of STAT3 and prevented IL-15 from decreasing neurite outgrowth. In conclusion, IL-15 may influence neural cell differentiation through a signal transduction pathway involving IL-15Ralpha and STAT3. This signal transduction modifies MAP-2 protein levels and, consequently, the differentiation of neurons from NSCs, as evidenced by reduced neurite outgrowth.

Involvement of SHP2 in focal adhesion, migration and differentiation of neural stem cells

OBJECTIVESnSHP2 (Src-homology-2 domain-containing protein tyrosine phosphatase) plays an important role in cell adhesion, migration and cell signaling. However, its role in focal adhesion, differentiation and migration of neural stem cells is still unclear.nnnMETHODSnIn this study, rat neurospheres were cultured in suspension and differentiated neural stem cells were cultured on collagen-coated surfaces.nnnRESULTSnThe results showed that p-SHP2 co-localized with focal adhesion kinase (FAK) and paxillin in neurospheres and in differentiated neural precursor cells, astrocytes, neurons, and oligodendrocytes. Suppression of SHP2 activity by PTP4 or siRNA-mediated SHP2 silencing caused reduction in the cell migration and neurite outgrowth, and thinning of glial cell processes. Differentiation-induced activation of FAK, Src, paxillin, ERK1/2, and RhoA was decreased by SHP2 inactivation.nnnCONCLUSIONSnThese results indicate that SHP2 is recruited in focal adhesions of neural stem cells and regulates focal adhesion formation. SHP2-mediated regulation of neural differentiation and migration may be related to formation of focal adhesions and RhoA and ERK1/2 activation.

Imaging serotonin transporters using [123I]ADAM SPECT in a parkinsonian primate model

Parkinsons disease (PD) affects multiple neurotransmitter systems. The purpose of this study was to investigate differences in the serotonin transport system between normal and parkinsonian monkeys using 2-([2-([di-methylamino]methyl)phenyl]thio)-5-[(123)I] iodophenyl-amine([(123)I]ADAM), a serotonin transporters (SERT) radioligand. The brain single photon emission computed tomography (SPECT) was performed on two normal and one parkinsonian monkey. The parkinsonian monkey was induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle under magnetic resonance imaging (MRI) guidance. Each monkey underwent two [(99m)Tc] TRODAT-1 (a dopamine transporters imaging agent) and two [(123)I] ADAM brain SPECT scans. After a bolus injection of the radioligand, the SPECT data were acquired over 4h using a dual-head gamma camera equipped with ultra-high resolution fan-beam collimators. The striatal uptake of [(99m)Tc]TRODAT-1 was 46% lower in the parkinsonian monkey than those of normal monkeys at 210-240 min post-injection. [(123)I]ADAM uptake in the midbrain of the parkinsonian monkey was comparable to those of the controls. The uptakes of [(123)I]ADAM in the striatum, thalamus, and frontal cortex of the parkinsonian monkey, were 31%, 31%, and 23% lower than those of normal monkeys at 210-240 min post-injection, respectively. Our results suggest that [(123)I]ADAM SPECT has potential for evaluating the serotonin transporter changes in human PD.

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

INTRODUCTIONnParkinsons disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging.nnnMETHODSnFour healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [(99m)Tc]TRODAT-1 (a dopamine transporter imaging agent) and [(123)I]ADAM (a serotonin transporter imaging agent).nnnRESULTSnThe results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [(99m)Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [(123)I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey.nnnCONCLUSIONSnOur results suggest that dual-isotope SPECT using [(99m)Tc]TRODAT-1 and [(123)I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

The Role of Molecular Imaging in the Diagnosis and Management of Neuropsychiatric Disorders

Neuropsychiatric disorders are becoming a major socioeconomic burden to modern society. In recent years, a dramatic expansion of tools has facilitated the study of the molecular basis of neuropsychiatric disorders. Molecular imaging has enabled the noninvasive characterization and quantification of biological processes at the cellular, tissue, and organism levels in intact living subjects. This technology has revolutionized the practice of medicine and has become critical to quality health care. New advances in research on molecular imaging hold promise for personalized medicine in neuropsychiatric disorders, with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, early diagnosis, and personal health planning. In this paper, we discuss the development of radiotracers for imaging dopaminergic, serotonergic, and noradrenergic systems and β-amyloid plaques. We will underline the role of molecular imaging technologies in various neuropsychiatric disorders, describe their unique strengths and limitations, and suggest future directions in the diagnosis and management of neuropsychiatric disorders.

Simultaneous [99mTc]TRODAT-1 and [123I]ADAM Brain SPECT in Nonhuman Primates

PurposeThis study examined the feasibility of simultaneous dopamine and serotonin transporter imaging using [123I]ADAM and [99mTc]TRODAT-1 single photon emission computed tomography (SPECT).ProceduresSimultaneous [123I]ADAM (185xa0MBq) and [99mTc]TRODAT-1 (740xa0MBq) SPECT was performed in three age-matched female Formosan rock monkeys. An asymmetric energy window was used for dual, and symmetric energy windows were used for single-isotope imaging. Oral fluoxetine (20xa0mg) and intravenous methylphenidate HCl (1xa0mg/kg) were given 24xa0h and 10xa0min, respectively, before dual-isotope SPECT to test imaging specificities of [123I]ADAM and [99mTc]TRODAT-1.ResultsComparable image quality and uptake ratios between dual- and single-isotope SPECT scans were found. Dual-isotope SPECT in fluoxetine-pretreated monkeys showed decreased uptake of [123I]-ADAM, but not of [99mTc]TRODAT-1. Dual-isotope SPECT in methylphenidate-pretreated monkeys showed decreased [99mTc]TRODAT-1 uptake without affecting [123I]-ADAM uptake.ConclusionSimultaneous [123I]-ADAM and [99mTc]TRODAT-1 SPECT appears promising in nonhuman primates and may provide a suitable preclinical model with further clinical implications.

The Research / Development and Medical Applications of Isotope and Radiation Technology in Taiwan

With the installation of H-/D- cyclotron in 1993, the Institute of Nuclear Energy Research (INER) has successfully developed radioisotopes such as 123I, 201Tl, 67Ga, and 18F. Up to now, 12 radiopharmaceuticals including 13C-urea for breath test of Helicobacter pylori infection produced by INER have been licensed by the Department of Health for commercial production and distribution in Taiwan. The INER’s cyclotron and radiopharmaceutical facilities are operated according to ISO- 9001 and cGMP. 201Tl-TlCl and 18F-FDG, etc., are supplied by INER to local hospitals. Some radiopharmaceuticals are produced for preclinical and clinical trials, such as 123I-ADAM, 123I-IBZM, 123I-MIBG and 111In-DTPAOctreotide, etc. INER also supplies several cold kits to the domestic market for 99mTc-labeled radiopharmaceuticals. 60Co irradiation is applied in several fields in Taiwan, including medicine, agriculture, and industries. Another application of irradiation is in fine arts and sciences treasured by the nation. Recently, the 60Co facility obtained ISO-9001 certification. In conclusion, the prospects of isotope and radiation application in Taiwan are promising, and will continuously benefit the people and the society in our country.