Excessive tau accumulation in the parieto-occipital cortex characterizes early-onset Alzheimer's disease

Cho, Hanna,Choi, Jae Yong,Lee, Seung Ha,Lee, Jae Hoon,Choi, Young-Chul,Ryu, Young Hoon,Lee, Myoung Sik,Lyoo, Chul Hyoung Elsevier 2017 Neurobiology of aging Vol.53 No.-

<P><B>Abstract</B></P> <P>Early-onset Alzheimer's disease (EOAD) is characterized by greater nonmemory dysfunctions, more rapid progression, and greater hypometabolism and atrophy than late-onset AD (LOAD). We sought to investigate the differences in tau accumulation patterns between early- and late-onset patients with AD and mild cognitive impairment (MCI). In 90 patients who completed <SUP>18</SUP>F-AV-1451 and <SUP>18</SUP>F-florbetaben positron emission tomography scans, only 59 amyloid-positive patients (11 EOAD, 10 EOMCI, 21 LOAD, and 17 LOMCI) were included in this study. We compared cortical <SUP>18</SUP>F-AV-1451 binding between each patient group and corresponding amyloid-negative age-matched controls. In contrast to no difference in cortical binding between the EOMCI and LOMCI groups, EOAD showed greater binding in the parieto-occipital cortex than LOAD. The parieto-occipital binding correlated with visuospatial dysfunction in the EOAD spectrum, whereas binding in the temporal cortex correlated with verbal memory dysfunction in the LOAD spectrum. Our findings suggest that distinct topographic distribution of tau may influence the nature of cognitive impairment in EOAD patients.</P>

First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

Cho, Hanna,Shin, Injae,Ju, Eunhye,Choi, Seunghye,Hur, Wooyoung,Kim, Haelee,Hong, Eunmi,Kim, Nam Doo,Choi, Hwan Geun,Gray, Nathanael S.,Sim, Taebo American Chemical Society 2018 Journal of medicinal chemistry Vol.61 No.18

<P>GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, <B>10d</B>, <B>10g</B>, and <B>11i</B>, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound <B>11i</B> is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, <B>10k</B> possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.</P> [FIG OMISSION]</BR>

Evaluation of the Coal Ash Leaching Procedures at Mine Reclamation Sites

( Hanna Cho ),( Joo-yang Park ) 한국폐기물자원순환학회(구 한국폐기물학회) 2016 한국폐기물자원순환학회 춘계학술발표논문집 Vol.2016 No.-

Numerous leaching procedures for coal ash have demonstrated that the quantity of the extracted major and trace elements can be extremely variable, depending on the nature of both the coal ash and the leaching solution. It is difficult to identify the suitable leaching method for coal ash according to the particular situation in the field area. Nevertheless, to reduce deviations between leaching test estimates in the laboratory and measurements in the field, the appropriate leaching test must be identified and the appropriate leaching procedures with the right conditions must be selected. Site-specific conditions must be given due attention in the selection of a leaching test for coal ash. In South Korea, there is one legal leaching procedure: KLP(Korea leaching procedures). To find suitable leaching procedures for using coal ash at mine reclamation sites in South Korea, several leaching procedures relative to coal ash were reviewed and evaluated. To evaluate KLP according to its release of coal ash elements by comparing it with that of other leaching methods, data on several leaching methods, such as KLP, TCLP(Toxicity characteristic leaching procedure), SPLP(Synthetic precipitation leaching procedure), and MWLP(Mine water leaching procedure) were collected and analyzed. It was observed from this research that the KLP might have underestimated the leaching potential of nearly each trace metal in the analysis. Also, KLP appeared to have in accurately predicted the long-term effect of coal ash in mine environments. Most Korean coal ashes have alkaline characteristics, and when their alkalinity has been exhausted, their leachate becomes acidic. There is no suitable leaching procedures for acid environments in Korea. Due to this fact, the pH of the MWLP buffer solution was lower than that of other procedures. MWLP effectively exhausts elements of coal ash and helps determine the long-term leaching behavior of waste placed in acid environments. Therefore, MWLP mab be a more appropriate leaching test for the environmental impact assessment of the use of coal ash at mine reclamation sites in Korea.

Quality Characteristics of Tomato Kochujang prepared with various amounts of Tomato Powder

Hanna Cho,MyungJoo Han 한국식생활문화학회 2017 한국식생활문화학회학술대회논문집 Vol.2017 No.11

Higher education affects accelerated cortical thinning in Alzheimer's disease: a 5-year preliminary longitudinal study

Cho, Hanna,Jeon, Seun,Kim, Changsoo,Ye, Byoung Seok,Kim, Geon Ha,Noh, Young,Kim, Hee Jin,Yoon, Cindy W,Kim, Yeo Jin,Kim, Jung-Hyun,Park, Sang Eon,Kim, Sung Tae,Lee, Jong-Min,Kang, Sue J.,Suh, Mee Kyun Cambridge University Press 2015 INTERNATIONAL PSYCHOGERIATRICS - Vol.27 No.1

<B>ABSTRACT</B><B>Background:</B><P>Epidemiological studies have reported that higher education (HE) is associated with a reduced risk of incident Alzheimer's disease (AD). However, after the clinical onset of AD, patients with HE levels show more rapid cognitive decline than patients with lower education (LE) levels. Although education level and cognition have been linked, there have been few longitudinal studies investigating the relationship between education level and cortical decline in patients with AD. The aim of this study was to compare the topography of cortical atrophy longitudinally between AD patients with HE (HE-AD) and AD patients with LE (LE-AD).</P><B>Methods:</B><P>We prospectively recruited 36 patients with early-stage AD and 14 normal controls. The patients were classified into two groups according to educational level, 23 HE-AD (>9 years) and 13 LE-AD (≤9 years).</P><B>Results:</B><P>As AD progressed over the 5-year longitudinal follow-ups, the HE-AD showed a significant group-by-time interaction in the right dorsolateral frontal and precuneus, and the left parahippocampal regions compared to the LE-AD.</P><B>Conclusion:</B><P>Our study reveals that the preliminary longitudinal effect of HE accelerates cortical atrophy in AD patients over time, which underlines the importance of education level for predicting prognosis.</P>

A thiophene-based blue-fluorescent emitting chemosensor for detecting indium (III) ion

Cho, Hanna,Chae, Ju Byeong,Kim, Cheal Elsevier 2018 Inorganic chemistry communications Vol.97 No.-

<P><B>Abstract</B></P> <P>A thiophene-based chemosensor <B>TP</B>, ((<I>Z</I>)-<I>N</I>′-(pyridine-2-ylmethylene)thiophene-2-carbohydrazide), was synthesized and characterized. <B>TP</B> showed a significant fluorescence enhancement only in the presence of In<SUP>3+</SUP>. Importantly, the detection limit was calculated to be 0.61 μM, which is the lowest one reported to date. Job plot and ESI-mass analyses indicated that two <B>TP</B> molecules bind to one In<SUP>3+</SUP> ion. In addition, the sensing mechanism of <B>TP</B> towards In<SUP>3+</SUP> was proposed as chelation-enhanced fluorescence (CHEF) effect from the theoretical calculations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Thiophene-based chemosensor <B>TP</B> was synthesized and characterized. </LI> <LI> <B>TP</B> showed high selectivity towards In<SUP>3+</SUP> by fluorescence turn-on. </LI> <LI> Detection limit (0.61 μM) is the lowest among fluorescence turn-on In<SUP>3+</SUP> chemosensors. </LI> <LI> Detecting mechanism for In<SUP>3+</SUP> was proposed as chelation-enhanced fluorescence (CHEF) effect. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Predominant subcortical accumulation of ¹⁸F-flortaucipir binding in behavioral variant frontotemporal dementia

Cho, Hanna,Seo, Sang Won,Choi, Jae Yong,Lee, Hye Sun,Ryu, Young Hoon,Lee, Myung Sik,Na, Duk L.,Kim, Hee Jin,Lyoo, Chul Hyoung PERGAMON PRESS LTD 2018 NEUROBIOLOGY OF AGING Vol. No.

<P><B>Abstract</B></P> <P>Behavioral variant frontotemporal dementia (bvFTD) is the most common form of frontotemporal dementia, and tau pathology can be found in 40%–50% of bvFTD patients. In this study, we sought to investigate <SUP>18</SUP>F-flortaucipir-binding patterns and their correlates in clinically diagnosed bvFTD patients by comparing with results for Alzheimer's disease (AD) patients. We enrolled 20 bvFTD, 20 AD, and 20 age-matched healthy subjects who underwent neuropsychological tests, magnetic resonance imaging, and tau positron emission tomography scans with <SUP>18</SUP>F-flortaucipir. Regional standardized uptake value ratios for the cerebral cortex and underlying white matter were compared between the 2 groups. The bvFTD patients showed increased <SUP>18</SUP>F-flortaucipir binding in the putamen and globus pallidus when compared to the healthy controls. In addition, bvFTD was associated with increased binding in the white matter regions underlying the frontal, anterior cingulate, and insula cortices. The bvFTD patients may exhibit predominantly subcortical <SUP>18</SUP>F-flortaucipir-binding pattern that is distinct from the patterns seen in AD patients. We hypothesize that the clinical characteristics of bvFTD patients may be attributable to the dysfunctional frontal-subcortical networks. However, concerns remain regarding unknown “off-target” binding in the white matter and the basal ganglia.</P>

¹⁸F-flortaucipir uptake patterns in clinical subtypes of primary progressive aphasia

Cho, Hanna,Kim, Hee Jin,Choi, Jae Yong,Ryu, Young Hoon,Lee, Myung Sik,Na, Duk L.,Seo, Sang Won,Lyoo, Chul Hyoung Elsevier 2019 Neurobiology of aging Vol.75 No.-

<P><B>Abstract</B></P> <P>We analyzed <SUP>18</SUP>F-flortaucipir uptake patterns and structural changes in patients with subtypes of primary progressive aphasia (PPA) using <SUP>18</SUP>F-flortaucipir positron emission tomography and volumetric magnetic resonance imaging. We enrolled 34 consecutive patients with PPA (10 nonfluent/agrammatic PPA [nfvPPA], 18 semantic variant PPA [svPPA], and 6 logopenic variant PPA [lvPPA], as well as 20 healthy controls, and 20 patients with Alzheimer's disease. <SUP>18</SUP>F-flortaucipir uptake was increased in the frontal cortex and underlying white matter, and subcortical nuclei in the 10 nfvPPA and 8 nfvPPA-amyloid-β (Aβ)− subgroup patients. In the svPPA patients (both the 13 svPPA-Aβ− and 5 svPPA-Aβ+), uptake generally increased in the widespread neocortex with left anterior temporal predominance. <SUP>18</SUP>F-flortaucipir uptake patterns in the 6 lvPPA and the 5 lvPPA-Aβ+ subgroup patients were similar to those seen in the patients with Alzheimer's disease with mild predominance in the left lateral temporal cortex. Cortical thinning in each PPA subtype corresponded with increased <SUP>18</SUP>F-flortaucipir uptake. <SUP>18</SUP>F-flortaucipir uptake patterns and cortical atrophy were distinct and corresponded to areas related to the specific language functions that are impaired in each subtype of PPA.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We compared <SUP>18</SUP>F-flortaucipir uptake and structural changes in PPA subtypes. </LI> <LI> Increased <SUP>18</SUP>F-flortaucipir uptake corresponds to areas related to language functions. </LI> <LI> Cortical thinning in each PPA subtype corresponded to increased <SUP>18</SUP>F-flortaucipir uptake. </LI> <LI> <SUP>18</SUP>F-flortaucipir uptake and cortical atrophy were distinct in each subtype of PPA. </LI> </UL> </P>

¹⁸F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome

Cho, Hanna,Baek, Min Seok,Choi, Jae Yong,Lee, Seung Ha,Kim, Joong Seok,Ryu, Young Hoon,Lee, Myung Sik,Lyoo, Chul Hyoung Ovid Technologies (Wolters Kluwer) - American Acad 2017 Neurology Vol.89 No.11

<B>Objective:</B><P>To investigate tau distribution in patients with corticobasal syndrome (CBS) using <SUP>18</SUP>F-AV-1451 PET.</P><B>Methods:</B><P>Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with <SUP>18</SUP>F-AV-1451 (for tau) and <SUP>18</SUP>F-florbetaben (for β-amyloid). We compared standardized uptake value ratio maps of the <SUP>18</SUP>F-AV-1451 PET images between the patients with CBS and controls.</P><B>Results:</B><P>Compared to controls, patients with CBS exhibited asymmetrically increased <SUP>18</SUP>F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased <SUP>18</SUP>F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. <SUP>18</SUP>F-AV-1451 binding in the precentral white matter correlated with motor severity.</P><B>Conclusions:</B><P><SUP>18</SUP>F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks.</P>

Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277

Cho, Hanna,Sengupta, Sandip,Jeon, Sean S. H.,Hur, Wooyoung,Choi, Hwan Geun,Seo, Hong-Seog,Lee, Byung Joo,Kim, Jeong Hun,Chung, Minhwan,Jeon, Noo Li,Kim, Nam Doo,Sim, Taebo American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.4

<P>We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1-6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4' hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1.</P>