Evaluation of Therapeutic Efficacy using [18F]FP-CIT in 6-OHDA-induced Parkinson's Animal Model

박장우,Yi Seul Choi,김동현,이은상,박찬우,정혜경,유란지 대한방사성의약품학회 2023 Journal of radiopharmaceuticals and molecular prob Vol.9 No.1

Parkinson's disease is a neurodegenerative disease caused by damage to brain neurons related to dopamine. Non-clinical animal models mainly used in Parkinson's disease research include drug-induced models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, and genetically modified transgenic animal models. Parkinson's diagnosis can be made using brain imaging of the substantia nigra-striatal dopamine system and using a radiotracer that specifically binds to the dopamine transporter. In this study, 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane was used to confirm the image evaluation cutoff between normal and parkinson's disease models, and to confirm model persistence over time. In addition, the efficacy of single or combined administration of clinically used therapeutic drugs in parkinson's animal models was evaluated. Image analysis was performed using the PMOD software. Converted to standardized uptake value, and analyzed by standardized uptake value ratio by dividing the average value of left striatum by the average value of right striatum obtained by applying positron emission tomography images to the atlas magnetic resonance template. The image cutoff of the normal and the parkinson's disease model was calculated as SUVR=0.829, and it was confirmed that it was maintained during the test period. In the three-drug combination administration group, the right and left striatum showed a high symmetry of more than 0.942 on average and recovered significantly. Images using 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane are thought to be able to diagnose and evaluate treatment efficacy of non-clinical Parkinson's disease.

흰쥐 흑질내 수산화도파민 주입으로 유도된 파킨슨병 모델에서 흑질과 선조체의 신경교세포 반응

양경원,성재훈,김문찬,이문용,이상원,최승진,박춘근,강준기,Yang, Kyung Won,Sung, Jae Hoon,Kim, Moon Chan,Lee, Moon Yong,Lee, Sang Won,Choi, Seung Jin,Park, Choon Keun,Kang, Joon Ki 대한신경외과학회 2001 Journal of Korean neurosurgical society Vol.30 No.6

Objectives : Parkinson's disease is a well-known neurodegenerative disease characterized by dopaminergic cell death in the substantia nigra. The reactive gliosis by activated astrocytes and microglias is no more regarded as a simple sequel of neuronal cell death. Microglial activation takes place in a stereotypic pattern with graded morphologic and functional(resting, activated and phagocytic) changes. In Parkinson's disease animal model, the degree of microglial activation along the nigro-striatal dopaminergic tract has not been studied intensively. The purpose of this study was to elucidate the characteristics of microglial reaction and to grade its degree of activation at substantia nigra and corpus striatum using 6-hydroxydopamine induced rat model of Parkinson's disease. Methods : Using Sprague-Dawley rat, parkinsonian model was made by 6-hydroxydopamine(OHDA) induced destruction of medial and lateral substantia nigra(SN). The rat was sacrificed 3-, 5-, 7-, 14- and 21-day-after operation. For control group, we injected saline with same manner and sacrificed 3-day after operation. With immunohistochemistry, we examined dopaminergic neuronal cells and microglial expression using tyrosine hydroxylase (TH) and OX-42 antibodies, respectively. Also we performed in situ hybridization for osteopontin, a possible marker of subset in activated microglia. Results : 1) In lesioned side of substantia nigra and corpus striatum, the TH immunoreactivity was markedly decreased in whole experimental groups. 2) Using optical densitometry, microglia induced immunoreactivity of OX-42 was counted at SN and corpus striatum. At SN, it was increased significantly on the lesioned side in control and all time-dependent experimental groups. At striatum, it was increased significantly in post lesion 3-day group only(p <0.05). Compared to control group, immunoreactivity of OX-42 on lesioned side was increased in groups, except post lesion 21-day group, at SN. Only post lesion 3-day group showed significance at striatum(p <0.05). Compared to SN region, immunoreactivity of OX-42 was much weaker in striatum. 3) Microscopically, the microglias showed typically different activation pattern. At SN, numerous phagocytic microglias were found at pars compacta and reticularis of lesion side. At striatum, no phagocytic form was found and the intensity of staining was much weaker. 4) At SN, the immunoreactivity of osteopontin showed definite laterality and it was markedly increased at pars compacta of lesion side with relatively short duration time. At striatum, however, it was not detected by in situ hybridization technique. Conclusion : The nigral 6-OHDA induced rat model of Parkinson's disease revealed several characteristic patterns of microglial reaction. At SN, microglias was activated shortly after direct neuronal damage and maintained for about three weeks. In contrast, despite of sufficient dopaminergic insufficiency at striatum, activation of microglias was trivial, and distinguished 3 day later. Antegrade slow neuronal degeneration is major pathophysiology in striatal dopaminergic deficiency. So, the acuteness of neuronal damage and consequential degree of neuronal degeneration may be important factor for microglial activation in neurodegenerative diseases such as Parkinson's disease. Additionally, osteopontin may be a possible marker for several subsets of activated microglia, possibly the phagocytic form.

수산화도파민으로 유발된 파킨슨씨병 모델 흰쥐의 행동학 및 면역조직화학적 특성에 관한 연구

장웅규,정천기,오창완,한대희,김현집,조자선,김용식,박찬웅 대한신경외과학회 1998 Journal of Korean neurosurgical society Vol.27 No.2

MPTP 투여 파킨슨병 마우스 모델에서 유전자 및 DNA methylation 변화 관찰

강소희,김중선,이지혜,문창종,김철 한약정보연구회 2021 한약정보연구회지 Vol.9 No.2

This study aimed to establish an integrated network of DNA methylation and RNA expression in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model and investigate epigenetically-regulated genes involved in PD development. In this model, MPTP impaired motor coordination as demonstrated by the rota-rod behavioral test. MPTP also decreased the expression of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) of mice. We conducted genome-wide CpG-DNA methylation profiling through methylated DNA immunoprecipitation microarray and RNA sequencing using two substantia nigra samples from mice with MPTP-induced Parkinson’s disease. We profiled genome-wide DNA methylation using Methyl-Seq and measured the transcriptome using RNA-Seq in murine SN in the following groups: vehicle-treated mice and MPTP-induced PD mice. In total, 280 differentially expressed genes were identified in association with the PD effect of MPTP. Among them, 201 were positively correlated, and 79 were negatively correlated downregulated genes. A total of 1,773 differentially methylated regions (DMRs) were identified between mice with control and MPTP-induced PD mice. Of these, 474 were hypermethylated, and 398 were hypomethylated DMR. A total of three interconnected genes, autophagy related 7 (atg7), tumor necrosis factor ligand superfamily member 12 (tnfsf12), and diglyceride kinase eta (dgkh), were identified from the integrated DNA methylation and gene expression networks involved Parkinson’s disease development. These results indicate that modulating just three genes can effectively control the development of Parkinson’s disease.

Lexicon and Grammar in Bilingual Individuals with Alzheimer’s Disease and Parkinson’s Disease: A Comparative Review

이미선,Eunkyu Lee 서울대학교 인지과학연구소 2022 Journal of Cognitive Science Vol.23 No.2

Given the number of bilingual individuals worldwide, many of patients with Alzheimer’s disease (AD) or Parkinson’s disease (PD) are bilinguals. Yet little is known about the consequences of the two neurodegenerative diseases on the language of bilingual patients. In this paper, we review the available data in the bilingual literature, specifically the decline of language in patients with AD and PD at the lexical and grammatical levels. Our literature search of three electronic databases identified nine articles on bilingual patients with AD and five on those with PD that analyzed the lexicon and grammar of these patients. The findings of these studies are inconsistent but suggest that AD and PD should affect both languages in bilingual patients. They also show a trend that AD results in greater difficulties with lexicon and L2 grammar, while PD affects L1 grammar to a greater extent. This pattern is as expected by the declarative/procedural model that each disease affects a distinct memory system.

Patient-specific pluripotent stem cell-based Parkinson’s disease models showing endogenous alpha-synuclein aggregation

( Yohan Oh ) 생화학분자생물학회 2019 BMB Reports Vol.52 No.6

After the first research declaring the generation of human induced pluripotent stem cells (hiPSCs) in 2007, several attempts have been made to model neurodegenerative disease in vitro during the past decade. Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is mainly characterized by motor dysfunction. The formation of unique and filamentous inclusion bodies called Lewy bodies (LBs) is the hallmark of both PD and dementia with LBs. The key pathology in PD is generally considered to be the alpha-synuclein (α-syn) accumulation, although it is still controversial whether this protein aggregation is a cause or consequence of neurodegeneration. In the present work, the recently published researches which recapitulated the α-syn aggregation phenomena in sporadic and familial PD hiPSC models were reviewed. Furthermore, the advantages and potentials of using patient-derived PD hiPSC with focus on α-syn aggregation have been discussed. [BMB Reports 2019; 52(6): 349-359]

Enhanced Efficacy of Human Brain-Derived Neural Stem Cells by Transplantation of Cell Aggregates in a Rat Model of Parkinson's Disease

Shin, Eun Sil,Hwang, Onyou,Hwang, Yu-Shik,Suh, Jun-Kyo Francis,Chun, Young Il,Jeon, Sang Ryong The Korean Neurosurgical Society 2014 Journal of Korean neurosurgical society Vol.56 No.5

Objective : Neural tissue transplantation has been a promising strategy for the treatment of Parkinson's disease (PD). However, transplantation has the disadvantages of low-cell survival and/or development of dyskinesia. Transplantation of cell aggregates has the potential to overcome these problems, because the cells can extend their axons into the host brain and establish synaptic connections with host neurons. In this present study, aggregates of human brain-derived neural stem cells (HB-NSC) were transplanted into a PD animal model and compared to previous report on transplantation of single-cell suspensions. Methods : Rats received an injection of 6-OHDA into the right medial forebrain bundle to generate the PD model and followed by injections of PBS only, or HB-NSC aggregates in PBS into the ipsilateral striatum. Behavioral tests, multitracer (2-deoxy-2-[$^{18}F$]-fluoro-D-glucose ([$^{18}F$]-FDG) and [$^{18}F$]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([$^{18}F$]-FP-CIT) microPET scans, as well as immunohistochemical (IHC) and immunofluorescent (IF) staining were conducted to evaluate the results. Results : The stepping test showed significant improvement of contralateral forelimb control in the HB-NSC group from 6-10 weeks compared to the control group (p<0.05). [$^{18}F$]-FP-CIT microPET at 10 weeks posttransplantation demonstrated a significant increase in uptake in the HB-NSC group compared to pretransplantation (p<0.05). In IHC and IF staining, tyrosine hydroxylase and human ${\beta}2$ microglobulin (a human cell marker) positive cells were visualized at the transplant site. Conclusion : These results suggest that the HB-NSC aggregates can survive in the striatum and exert therapeutic effects in a PD model by secreting dopamine.

Modeling α-synuclein propagation with Preformed Fibril Injection

정현경,Hoang-Anh Ho,Dayana Perez-Acuña,이승재 대한파킨슨병및이상운동질환학회 2019 Journal Of Movement Disorders Vol.12 No.3

The aggregation of α-synuclein (α-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Postmortem analyses of α-syn pathology, especially that of PD, have suggested that aggregates progressively spread from a few discrete locations to wider brain regions. The neuron-to-neuron propagation of α-syn has been suggested to be the underlying mechanism by which aggregates spread throughout the brain. Many cellular and animal models has been created to study cell-to-cell propagation. Recently, it has been shown that a single injection of preformed fibrils (PFFs) made of recombinant α-syn proteins into various tissues and organs of many different animal species results in widespread α-syn pathology in the central nervous system (CNS). These PFF models have been extensively used to study the mechanism by which aggregates spread throughout the brain. Here, we review what we have learned from PFF models, describe the nature of PFFs and the neuropathological features, neurophysiological characteristics, and behavioral outcomes of the models.

Modeling Parkinson’s disease in the common marmoset (Callithrix jacchus): overview of models, methods, and animal care

윤준원,안재범,강병철 한국실험동물학회 2015 Laboratory Animal Research Vol.31 No.4

The common marmoset (Callithrix jacchus) is a small-bodied, popular New World monkey and is used widely in reproductive biology, neuroscience, and drug development, due to its comparative ease of handling, high reproductive efficiency, and its unique behavioral characters. In this review, we discuss the marmoset models in Parkinson’s disease (PD), which is a neurological movement disorder primarily resulting from a degeneration of dopaminergic neurons with clinical features of tremor, rigidity, postural instability, and akinesia. The most common PD models involve the administration of 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine to study the pathogenesis and to evaluate novel therapies. Following the systemic or local administration of these neurotoxins, the marmosets with very severe Parkinson's symptoms are recommended to be placed in an intensive care unit with artificial feeding to increase survival rate. All procedures with MPTP should be conducted in a special room with enclosed cages under negative-pressure by trained researchers with personal protection. Behavioral tests are conducted to provide an external measure of the brain pathology. Along with several biomarkers, including α-synuclein and DJ-1, non-invasive neuroimaging techniques such as positron emission tomography and magnetic resonance imaging are used to evaluate the functional changes associated with PD. With the recent growing interest in potential and novel therapies such as stem cell and gene therapy for PD in Korea, the marmoset can be considered as a suitable non-human primate model in PD research to bridge the gap between rodent studies and clinical applications.

Examining the Item-Level Psychometric Properties of the Communicative Effectiveness Survey-Revised for People with Parkinson’s Disease and Dysarthria

Neila J. Donovan 한국언어재활사협회 2018 Clinical Archives of Communication Disorders Vol.3 No.1

Purpose: To examine the psychometric properties of the Communicative Effectiveness Survey-Revised (CESR), a patient reported outcome measure of communicative effectiveness for people with Parkinson’s disease (PD) and dysarthria using Rasch analysis, a one-parameter logistic probability model based on principles of scientific measurement. Methods: 60 individuals with PD and hypokinetic dysarthria rated their communicative effectiveness on a 27-item, 4-point equal interval scale. Exploratory Factor Analysis (EFA) was run to determine unidimensionality. Rasch analysis was completed using the rating scale model. The various analyses allow researchers to examine the item-level psychometric properties of the CESR, which result in measures of validity, reliability and sensitivity. Results: The EFA demonstrated a single linear construct (confirmed unidimensionality) which allowed Rasch analysis to proceed. Results indicated: the theoretical item difficulty hierarchy established a priori had a strong positive correlation with the CESR item difficulty hierarchy, indicative of construct validity; the 4-unit rating scale comprised equal intervals; the match between person ability and item difficulty was near the ideal range, indicative of content validity; person reliability (comparable to Cronbach’s alpha) was strong; 4) the CESR separated respondents into 4 statistically significant ability levels, indicative of respondent reliability and sensitivity of the measure; and no ceiling or floor effects existed, although participants demonstrated a wide range of ability. Conclusions: The CESR demonstrated strong item-level psychometric properties which were indicative of validity, reliability and sensitivity of the scale for use with individuals with PD and dysarthria. Further testing must be completed to determine cutoff and clinically meaningful difference scores.