Jae-Jun Lee

Gd‐DOTA Conjugate of RGD as a Potential Tumor‐Targeting MRI Contrast Agent

Targeted delivery of contrast agents (CAs) with specific tumor recognition sites and simultaneous monitoring of the growth and metastasis of tumors in the body is an important goal in diagnostic molecular imaging. RGD (Arg-Gly-Asp) peptide is well known to have a relatively high and specific affinity for anb3-integrin, which is over-expressed in nascent endothelial cells during angiogenesis (formation of new blood vessels) in various tumor types and not in inactive endothelial cells. The expression of an endothelial anb3-integrin has been shown to correlate with tumor grade and thus plays a significant role in diagnosis of tumors. Some progress in tumor-targeted imaging by positron emission tomography (PET) or near-infrared fluorescence (NIRF) has recently been made with the aid of RGD complexes labeled with radioactive isotopes or fluorescent tags. Despite the usefulness of PET and NIRF, their applications are rather limited because of inherent problems such as light scattering, the invasive nature of data collection, photo-bleaching, and poor resolution. Molecular magnetic resonance imaging (MRI), however, can not only overcome these restrictions, but, with the assistance of a CA that catalytically shortens the relaxation time of the protons of nearby water molecules, can also provide excellent anatomy images. Thermodynamically stable, water-soluble, and highly paramagnetic Gd complexes, each bearing a multidentate ligand and at least one coordinated water molecule, have demonstrated high relaxivity and have therefore served as versatile MRI CAs. Among the early MRI CAs approved for clinical use are Dotarem and Omniscan . These Gd complexes incorporate the macrocycle 1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid (DOTA) as ligand and exhibit high thermodynamic stability. The fact that DOTA can employ at least one carboxylate to form a conjugate with a peptide such as RGD provides additional advantages for the preparation of targetspecific MRI CAs. In this regard, GdACHTUNGTRENNUNG(DOTA) conjugated with RGD should be an attractive candidate as a paramagnetic MRI CA for tumor-targeting. We now therefore wish to introduce the Gd ACHTUNGTRENNUNG(DOTA) conjugate of RGD, designed to monitor the activation of anb3-integrin in tumor tissue. The synthesis initially involved conjugation of DOTA and the cyclic pentapeptide c ACHTUNGTRENNUNG(RGDYK) as described by others. The DOTA-RGD conjugate thus prepared was purified and isolated by preparative HPLC. The Gd-DOTA-RGD complex was prepared by treatment of the DOTA-RGD with GdCl3·6 H2O in water. The final product was isolated as a white solid after purification by preparative HPLC. MALDI-TOF-MS shows a peak corresponding to [M+H H2O] (m/z 1161.50; calculated MW for C43H67GdN13O16 = 1178.39). The proton relaxivities—R1 and R2—of Gd-DOTA-RGD are 7.4 0.20 mm 1 s 1 and 4.0 0.24 mm 1 s , respectively at 298 K and 64 MHz. Gd-DOTA-RGD exhibits higher longitudinal relaxivity than small-molecule MRI CAs (for the data see the Supporting Information), which may be explained in terms of slower molecular tumbling (tg) as a result of the increase in molecular weight achieved through conjugation with RGD. In [a] J.-A. Park, J.-J. Lee, Prof. Y. Chang Department of Medical and Biological Engineering Kyungpook National University Daegu 702-701 (Korea) [b] Prof. J.-C. Jung Department of Biology, Kyungpook National University Daegu 702-701 (Korea) [c] Dr. D.-Y. Yu Korea Research Institute of Bioscience and Biotechnology Daejeon 305-806 (Korea) [d] Prof. C. Oh Department of Dermatology, College of Medicine, Korea University Seoul 152-703 (Korea) [e] Prof. C. Oh, S. Ha Research Institute for Skin Image College of Medicine, Korea University Seoul 152-703 (Korea) [f] Prof. T.-J. Kim Department of Applied Chemistry, Kyungpook National University Daegu 702-701 (Korea) Fax: (+ 82) 53-950-6594 E-mail : tjkim@knu.ac.kr [g] Prof. Y. Chang Department of Diagnostic Radiology and Molecular Medicine Kyungpook National University Daegu 702-701 (Korea) Fax: (+ 82) 53-422-2677 E-mail : ychang@knu.ac.kr Supporting information for this article is available on the WWW under http ://www.chembiochem.org or from the author.

Working Memory Impairment in Fibromyalgia Patients Associated with Altered Frontoparietal Memory Network

Background Fibromyalgia (FM) is a disorder characterized by chronic widespread pain and frequently associated with other symptoms. Patients with FM commonly report cognitive complaints, including memory problem. The objective of this study was to investigate the differences in neural correlates of working memory between FM patients and healthy subjects, using functional magnetic resonance imaging (MRI). Methodology/Principal Findings Nineteen FM patients and 22 healthy subjects performed an n-back memory task during MRI scan. Functional MRI data were analyzed using within- and between-group analysis. Both activated and deactivated brain regions during n-back task were evaluated. In addition, to investigate the possible effect of depression and anxiety, group analysis was also performed with depression and anxiety level in terms of Beck depression inventory (BDI) and Beck anxiety inventory (BAI) as a covariate. Between-group analyses, after controlling for depression and anxiety level, revealed that within the working memory network, inferior parietal cortex was strongly associated with the mild (r = 0.309, P = 0.049) and moderate (r = 0.331, P = 0.034) pain ratings. In addition, between-group comparison revealed that within the working memory network, the left DLPFC, right VLPFC, and right inferior parietal cortex were associated with the rating of depression and anxiety? Conclusions/Significance Our results suggest that the working memory deficit found in FM patients may be attributable to differences in neural activation of the frontoparietal memory network and may result from both pain itself and depression and anxiety associated with pain.

Altered working memory process in the manganese-exposed brain.

Chronic manganese (Mn) exposure often leads to impairments in fine motor and cognitive functions, particularly memory. However, the neural correlates of Mn-induced alterations in memory remain unclear. In the present study, we performed functional MRI (fMRI) with 2-back memory tests to assess the neural correlates of Mn-induced memory impairment in response to subclinical dysfunction in the working memory networks in welders exposed to Mn for extended periods of time. Within-group and between-group analyses revealed that brain activity in working memory networks was increased in welders with chronic Mn exposure during the 2-back verbal working memory task compared to healthy control individuals. Therefore, our fMRI findings indicate that welders might require more neural resources in working memory networks to compensate for subtle deficits in working memory and altered working memory processes, even if they performed the tasks at the same level as healthy control individuals.

Neural correlates of motor imagery for elite archers

Motor imagery is a mental rehearsal of simple or complex motor acts without overt body movement. It has been proposed that the association between performance and the mental rehearsal period that precedes the voluntary movement is an important point of difference between highly trained athletes and beginners. We compared the activation maps of elite archers and nonarchers during mental rehearsal of archery to test whether the neural correlates of elite archers were more focused and efficiently organised than those of nonarchers. Brain activation was measured using functional MRI in 18 right‐handed elite archers and 18 right‐handed nonarchers. During the active functional MRI imagery task, the participants were instructed to mentally rehearse their archery shooting from a first‐person perspective. The active imagery condition was tested against the nonmotor imagery task as a control condition. The results showed that the premotor and supplementary motor areas, and the inferior frontal region, basal ganglia and cerebellum, were active in nonarchers, whereas elite archers showed activation primarily in the supplementary motor areas. In particular, our result of higher cerebellar activity in nonarchers indicates the increased participation of the cerebellum in nonarchers when learning an unfamiliar archery task. Therefore, the difference in cerebellar activation between archers and nonarchers provides evidence of the expertise effect in the mental rehearsal of archery. In conclusion, the relative economy in the cortical processes of elite archers could contribute to greater consistency in performing the specific challenge in which they are highly practised. Copyright

Evaluation of white matter structures in patients with tinnitus using diffusion tensor imaging.

Recent functional imaging studies have demonstrated that the sensation of tinnitus is associated with activity in cortical regions functionally linked to subserve the generation, perception and processing of the tinnitus stimulus. Previous functional imaging studies have focused primarily on the cortical centers. However, none of these examined the functional nature of associated white matter interconnecting these cortical centers. In this study, we investigate the integrity of white matter tracts interconnecting the auditory system to the parietal and frontal corticies in tinnitus patients using diffusion tensor imaging. Our preliminary results suggest the possible involvement of associated white matter structures in addition to processing cortical centers in tinnitus patients compared with healthy subjects.

Altered white matter microstructural integrity revealed by voxel-wise analysis of diffusion tensor imaging in welders with manganese exposure.

Chronic exposure to manganese (Mn), which can be an occupational hazard or can result from liver failure, is associated with adverse motor and cognitive outcomes. Evidence from previous neuroimaging and magnetic resonance spectroscopy studies suggested alteration of function in Mn-exposed brains. However, the effect of chronic exposure of the human brain to Mn on white matter (WM) structure has not yet been determined. In the present study, we used diffusion tensor imaging (DTI) to investigate whether welders exposed to Mn demonstrate differences in WM integrity, compared with control subjects. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured on a voxel-wise basis in 30 male welders with exposure to Mn and in 19 age- and gender-matched control subjects. Direct comparison between welders and controls using investigator-independent Statistical Parametric Mapping (SPM) voxel-wise analysis of DTI metrics revealed a reduction of FA in the corpus callosum (CC) and frontal WM in Mn-exposed welders. Further, marked increases in RD and negligible changes in AD suggested that the microstructural changes in the CC and frontal WM result from compromised radial directionality of fibers in these areas, caused primarily by demyelination. Correlation analysis with neurobehavioral performance also suggested that the microstructural abnormalities were associated with subtle motor and cognitive differences in welders.

Alterations in cortical activity of male methamphetamine abusers performing an empathy task: fMRI study.

We investigate possible differences in neural correlates of empathy processing between abstinent methamphetamine (MA) abusers and healthy subjects using functional magnetic resonance imaging (fMRI).

Reduced corpus callosum white matter microstructural integrity revealed by diffusion tensor eigenvalues in abstinent methamphetamine addicts

The purpose of the current study was to determine whether abstinent methamphetamine (MA) abusers demonstrate differences in white matter (WM) integrity of the corpus callosum (CC) due to possible neurotoxic effects of long-term MA abuse, compared with control subjects. In addition to fractional anisotropy (FA), the eigenvalues of the diffusion ellipsoid were used to evaluate the microstructural source of abnormal change in abstinent MA abusers if there occurred a difference in white matter integrity of the CC between healthy controls and abstinent MA abusers. Results showed significantly reduced FA in the genu of the corpus callosum in MA-dependent subjects compared with controls. Furthermore, the eigenvalues offered a unique opportunity to assess the microstructural source of abnormal changes in the genu of the CC. The relationships between Wisconsin Card Sorting Test (WCST) performance and the values of tensor measures also suggest that altered myelination is a possible source of FA reduction observed in the genu of the CC in MA abusers.

The differences in neural network activity between methamphetamine abusers and healthy subjects performing an emotion-matching task: functional MRI study

Methamphetamine (MA) abusers commonly exhibit socially problematic behaviors, such as diminished empathy, decreased emotional regulation and interpersonal violence, which may be attributable to alterations in emotional experience. However, few studies have used functional MRI to examine directly the emotional experience of threatening or fearful non‐face images in MA abusers. In this study, we investigated possible differences in neural correlates of negative emotional experiences between abstinent MA abusers and healthy subjects using complex visual scenes depicting fear or threat derived from the International Affective Picture System. In within‐group analyses, healthy subjects and MA abusers activated a similarly distributed cortical network, prominently including the amygdala, fusiform gyrus, parahippocampal gyrus, ventrolateral prefrontal cortex and inferior frontal cortex. In between‐group analyses, however, MA abusers showed a reduced activation in the bilateral dorsolateral prefrontal cortex and insula, and increased activation in the fusiform gyrus, hippocampus, parahippocampal gyrus and posterior cingulate cortex, relative to healthy subjects. Hypoactivation of the insula in MA abusers relative to healthy subjects suggests that the ability to have an emotional response to threatening scenes and empathy for anothers pain could be compromised in MA abusers. Hyperactivity in the fusiform gyrus, parahippocampal gyrus and posterior cingulate cortex in MA abusers relative to healthy subjects indicates that threatening and fearful images from the International Affective Picture System may remind MA abusers of episodic memory related to similar experiences. Therefore, functional impairment of these neural networks in MA abusers may contribute to altered emotional experience in social interactions, which could lead to increased negative mood and stress in interpersonal communication. Copyright

Pallidal index measured with three-dimensional T1-weighted gradient echo sequence is a good predictor of manganese exposure in welders.

To evaluate which T1‐wieghted technique between 3D gradient‐echo (FSPGR) and conventional spin‐echo (SE) sequence is more sensitive predictor of neurobehavioral dysfunction found in welders with chronic manganese (Mn) acquired at 3 Tesla.