Astrocytic TRPV1-induced endogenous neurotrophic factors protect dopaminergic neuron in Parkinson’s disease

김경인 경희대학교 대학원 2019 국내박사

Recently capsaicin (CAP) neuroprotection of dopamine (DA) neurons by astrocytic transient receptor potential vanilloid 1 (TRPV1) derived ciliary neurotrophic factor (CNTF) in MPP+ rat model of Parkinson’s disease (PD). Apart from CNTF, other neurotrophic factors associated with DA neuron were produced via astrocytic TRPV1 in MPP+-lesioned or α-syn-lesioned rat. Here I determined that among these neurotrophic factors, cerebral dopamine neurotrophic factor (CDNF) expressed by activation of TRPV1 prevented degeneration of DA neurons in MPP+-lesioned or α-syn-lesioned rat and improved amphetamine-induced rotational behavior. Astrocytic CDNF knockdown by shCDNF attenuated capsaicin-induced neuroprotection and behavioral recovery, indicating that astrocytic TRPV1-derived endogenous CDNF has neuroprotective properties in MPP+-lesioned rat. Collectively, these results indicate that astrocytic TRPV1 as the endogenous neuroprotective machinery in vivo might produce various neurotrophic factors required for DA neuron survival and have a promising therapeutic target for the treatment of PD.

파킨슨병 침치료 임상진료지침 개발을 위한 기초 연구

강두희 경희대학교 대학원 2010 국내석사

Background: Parkinson's disease is characterized by resting tremor, rigidity, bradykinesia and postural instability. It is the most common neurodegenerative disorder after Alzheimer's disease and is being newly recognized with the increase in elderly population and an increased interest in health. Symptomatic medication and operative methods have been unable to provide a complete recovery and complications arise with the progression of the disease. Over the years oriental medicine has treated and delayed the clinical progression of symptoms similar to Parkinson's disease. Recent studies have shown the potential of acupuncture treatment but the need for a medical guideline for Parkinson's disease acupuncture treatment is ever present. Objective and Methods: This study is a preliminary study to develop a medical guideline for Parkinson's disease acupuncture treatment. Using evidence based development methods, a general literature review was done to arrange and understand knowledge on Parkinson's disease and a systematic review was done to search, evaluate and integrate 11 rct, 7 clinical trials, 7 case reports and 13 animal experiments from articles on Parkinson's disease acupuncture treatment released domestically and overseas. The following conclusions regarding the treatment regimen according to the degree of progression of Parkinson's disease, acupuncture treatment frequency, acupuncture treatment period, evaluation period and method, acupuncture stimulation method, acupoints were reached. Conclusions: Treatment regimen according to the degree of progression of Parkinson's disease - If the patient is not experiencing difficulty living everyday life and has no problems maintaining a job, symptomatic medical treatment should be discontinued where possible and acupuncture treatment along with neuroprotective medication should be administered. If the patient has difficulty living everyday life or maintaining a job then symptomatic medical treatment together with acupuncture treatment was suggested. Acupuncture treatment frequency - Twice a week as an outpatient, seven times a week if hospitalized was suggested. Acupuncture treatment period - Since continuous management is required the improvement should be evaluated every 4 weeks and if there is improvement in the patients subjective symptoms, H-Y stage(Hoehn & Yahr Stage), ADL scale(Schwab and England activity of daily living) then acupuncture is considered to be significant and should be continued. Acupuncture stimulation method - Manual acupuncture and electroacupuncture can be administered together. Treatment acupoints - In addition to general standard acupoints GV20, LI4, LI11, LR3, ST36, GB34, acupoints can be selected according to symptom differentiation, and or sasang constitution. Additional acupoints can be supplemented according to chief motor symptoms, non-motor Parkinsonian symptoms, and complications from antiparkinsonian agents. With the conclusions stated above, a draft for the development of medical guideline for Parkinson's disease acupuncture treatment has been written up and suggested. Using this study as a foundation, if a medical guideline for parkinson's disease acupuncture treatment is developed by expert agreement, it will contribute greatly to Parkinson's disease treatment in a clinical setting and is expected to improve the quality of life of patients with Parkinson's disease. Additional studies should be continued to accumulate quality evidence. Key Words : Parkinson's disease, Acupuncture, Medical guideline

Low-intensity transcranial ultrasound and Mucuna Pruriens for treatment of Parkinson’s disease in mice

Zaigham Sheher Bano Graduate school Jeju National University 2023 국내석사

Parkinson’s disease (PD) is the second leading neurodegenerative disease after Alzheimer’s disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain and aggregation of the alpha synuclein, resulting in motor, non-motor, and olfactory impairment of the body. Mucuna Pruriens (MP) is a nutraceutical product which contains Levodopa (L-DOPA) and has proven effects in improving the symptoms of PD. Moreover, low-intensity transcranial ultrasound (LITUS) can activate neurons to release dopamine and help in alleviating the symptoms of PD. In this study, we investigated the anti-parkinsonian potential of MP and LITUS against PD. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. The number of mice used in this experiment was 32. There were 2 phases of mice experiment. The 1st phase of the experiment was performed to investigate MP effects on PD mice compared with the L-DOPA. These experiments were performed to validate the effectiveness of MP to treat PD in relation to standard treatment of PD. For that purpose, synthetic L-DOPA in a ratio of 1:20 with MP was used as it contains 5% L-DOPA by weight in it. 12 mice were used in this phase and were divided into 4 groups of 3 mice such as control group, PD group, PD treated with MP and PD treated with L-DOPA. The 2nd phase was performed to investigate the effect of MP and LITUS individually and collectively on PD mice. 20 mice were divided into 5 groups of 4 mice which were control, PD, PD with MP, PD treated with LITUS and PD treated with both MP and LITUS groups. The PD was induced in 28 days while PD treatment lasted for 19 and 10 days in the 1st and 2nd phases, respectively. Beam balance test, olfactory test, and serum enzyme-linked immunosorbent assay (ELISA) analysis test for IL-12, IL-6, TGF-β1 was performed to validate the PD inducement and treatment. The levels of IL-12, IL-6 and TGF-β1 (p<0.0001) in PD mice model group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p<0.0001) as compared to the control group. In the 1st phase, both MP and L-DOPA treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p<0.001). The results treated by MP and L-DOPA showed insignificant difference in their values (p>0.05). This proved that the MP and L-DOPA have similar effects in improving the symptoms of PD when used in the ratio of 1:20. In the 2nd phase, after being treated with MP the level of IL-6 (p<0.05), TGF-β1 (p<0.001) and IL-12 (p<0.0001) were significantly reduced as compared to untreated PD mice. While treatment with LITUS also downregulated the levels of IL-6 (p<0.01), TGF- β1 (p<0.001) and IL-12 (p<0.01) as compared to untreated PD mice. The PD mice treated by the MP+LITUS showed less latency (p<0.05) and less time (p<0.001) as compared to untreated PD mice during beam balance and olfactory tests, respectively. These results proved the effectiveness of both MP and LITUS in reducing the level of neuroinflammation and improving the behavioral symptoms in PD mice model. Moreover, PD mice being treated with MP and LITUS collectively showed better results in olfactory test but not for other factors as compared to untreated PD mice. These findings suggest that each MP and LITUS may have a potential therapeutic effect on PD but not much synergically by modulating the inflammatory response of the body. Furthermore, both MP and LITUS reduced the level of IL-6 and TGF-β1 in this study. It may be inferred that reduction in the level of IL-6 and TGF-β1 eventually leads to the reduction of the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP and LITUS in ameliorating the PD symptoms. 

Bimanual Motor Impairments in Patients with Parkinson’s Disease

이한얼 인천대학교 대학원 2024 국내박사

Parkinson’s disease is a neurological disorder that causes motor symptoms such as tremor, rigidity, and bradykinesia. In the early stages of Parkinson’s disease, motor symptoms may occur asymmetrically, and patients may experience deficits on bimanual force control capability and bimanual coordination. The purpose of this study was to investigate motor impairments in patients with PD by using an isometric force control paradigm for fine motor control assessment, such as bimanual force control capabilities and bimanual force coordination. 33 patients with early stage PD and 33 age matched healthy older adults were recruited to estimate bimanual force control capabilities, bimanual force coordination, bimanual force control asymmetry and bimanual motor dexterity. To evaluate bimanual force control capabilities, bimanual isometric force control task was conducted at target force levels at 10% and 40%MVC, based on each individual's maximum voluntary contraction (MVC). The analysis included assessments of mean force, accuracy, variability, and regularity. For assessing bimanual coordination, within-trial analyses included the coefficient of variation and cross-correlation, and between-trial analyses using uncontrolled manifold analysis were conducted. Additionally, to assess bimanual motor dexterity in patients with Parkinson's disease, bimanual Pegboard tasks were conducted. The result indicated that PD group showed lower mean force, lower force accuracy, higher force variability and higher force regularity in bimanual force control capabilities. Additionally, PD group exhibited lower bimanual Pegboard test scores on bimanual motor dexterity. For bimanual force coordination, PD group revealed lower bilateral motor synergy as compared with CON group. Further, negative correlations were found between bimanual force control capabilities and UPDRS-III subscores, bimanual coordination and UPDRS-III subscores, and bimanual dexterity scores and UPDRS-III subscores for correlation analyses. These findings suggest that early and precise assessment of fine motor control may be crucial for developing potential rehabilitation protocols in patients with early stage of PD. 파킨슨병 환자들의 양손 운동기능 손상 파킨슨병은 중추신경계 질환으로 뇌의 흑색질 부위에 존재하는 신경세포의 사멸 로 도파민의 생성이 정상적으로 되지 않음으로 인해 파킨슨병 운동증상(예: 떨림, 강직성, 완만증, 자세유지 및 걸음걸이 장애)이 발생한다. 초기 단계의 파칸슨병 운 동증상은 편측성으로 발생하게 되며, 파킨슨병 환자들의 힘조절 능력에 있어 대칭 성이 무너질 수 있다. 운동 비대칭성은 양측이 동반되는 협응성이 요구되는 동작의 저하로 이어지게 되며 양손 힘조절능력 및 이와 연관된 양손 협응성 저하가 발생할 수 있다. 본 연구의 목적은 등척성 힘조절 패러다임을 통해 파킨슨병 환자들의 양 손 힘조절능력 및 협응성과 연관된 운동손상을 평가하는 데 있다. 이를 위해 초기 단계에 해당하는 파킨슨병 환자 33명, 건강한 노인 33명을 대상으로 양손 힘조절능 력, 양손 협응성 및 양손 손재주를 평가하였다. 양손 힘조절능력을 평가하기 위해 개인 악력의 최대 자발적 수축(maximum voluntary contraction; MVC)의 측정을 이용 한 개인이 힘조절을 통해 도달해야 될 목표 힘수준의 생성 10%MVC 및 40%MVC 에 따른 등척성 힘조절 과제를 실시하여 평균 힘, 정확성, 가변성, 규칙성을 분석하 였다. 양손 협응성을 평가하기 위해 시도 내 분석에 해당하는 변동계수, 상호상관성 그리고 시도 간 분석인 비제어다양체 분석을 실시했다. 또한, 파킨슨병 환자들의 양 손 손재주를 평가하기 위해 팩보드를 이용한 양손 손재주 점수를 평가하였다. 추가 적으로 양손 힘조절능력, 손재주 및 임상 운동성 평가 점수 간 상관관계를 각각 분 석하였다. 연구결과, 파킨슨병 환자의 양손 힘조절능력에서 낮은 힘 정확성, 높은 힘 가변성, 높은 힘 규칙성이 나타났으며 양손 손재주 평가 점수의 경우 대조군과 비교하여 낮게 나타났다. 양손 협응성 변인에서 낮은 양측운동시너지가 나타났다. 또한, 상관관계 분석결과에서 양손 힘조절능력 변인 및 임상 운동성 평가 점수 간 음의 상관관계, 양손 협응성 및 임상 운동성 평가 점수 간 음의 상관관계, 그리고 양손 손재주 점수 및 임상 운동성 평가 점수 간 음의 상관관계가 나타났다. 이러한 결과로써 초기 단계 파킨슨병 환자의 미세 힘조절과 연관된 운동손상 평가는 중요 하며, 이와 연관된 재활프로토콜 개발에 있어 필수적인 기초자료가 될 수 있다. 주제어: 파킨슨병, 양손 힘조절능력, 양손 협응성, 손재주 평가, 임상 운동성 평가

Effects of genetic rare variants on Parkinson's disease in the Korean population

김원찬 Graduate School, Yonsei University 2013 국내박사

Background: The genetic background of a disease is usually explained by either rare mutations in a disease-causing gene or common susceptibility alleles that increase risk for a disease. A number of causative or susceptibility genes have been discovered for familial and idiopathic Parkinson’s disease. Although mutations in PARK2 are known to be the most common autosomal recessive gene for early onset Parkinson’s disease, these mutations are rare in Asians. Moreover, there is still much debate about whether a single heterozygous PARK2 mutation is a risk factor for Parkinson’s disease. There are very few patient-control gene-dosage studies for PARK2, and notably there has been only 1 study on the Asian population. Mutation in the glucocerebrosidase (GBA) gene is a causal mutation for Gaucher’s disease; however, many different ethnic populations have a heterozygous carrier of this mutation, which has a 3-fold higher risk for Parkinson’s disease. There have been no studies on the effect of the GBA mutation on Parkinson’s disease in the Korean population, although given that Gaucher’s disease is extremely rare in Korea, a heterozygous mutation of GBA might not be a risk allele. The purpose of this study was to investigate whether rare variants of GBA or PARK2 are linked to Parkinson’s disease in the Korean population. Methods: The frequency of the GBA mutation was compared between patient and control populations in order to determine whether a heterozygous mutation in GBA is associated with Parkinson’s disease in the Korean population. Common GBA mutations in the Korean population were also determined. GBA mutations were assessed in 277 PD patients and 291 normal control subjects. All exons of the GBA gene were analyzed in all patients and in 100 normal control subjects. Exons 2 and 5?11, where mutations were observed in the patient population, were further analyzed in 191 additional normal control subjects. To investigate whether a single heterozygous mutation of PARK2 is associated with Parkinson’s disease, the gene dosage of all exons of PARK2 was analyzed in patients with early onset and familial Parkinson’s disease and control subjects. Dosage analysis of mutations in the PARK2 gene was performed in 188 early onset or familial Parkinson’s disease patients and 191 normal control subjects by using real-time polymerase chain reaction. In patients who showed a heterozygous gene-dosage mutation, sequence analysis was performed to exclude the possibility of complex heterozygous mutations. Results: GBA mutation analysis revealed 5 heterozygous mutations, N188S, P201H, R257Q, S271G, and L444P, in 9 (3.2%) Parkinson’s disease patients. No GBA mutations were detected in the normal control group (p < 0.01; odds ratio, 20.6; 95% confidence interval, 1.2?356.4). The patients with a heterozygous GBA mutation showed a significantly earlier onset of disease than the patients without the mutation (48.6 ± 11.9 vs. 57.9 ± 13.5; p < 0.05; Mann?Whitney test). Analysis of the PARK2 mutation revealed that 21 (11.2%) patients had a mutation in PARK2. Of them, five (23.8%) patients had compound heterozygous mutations and 13 (61.9%) had a heterozygous mutation. Among 29 mutated alleles, one small sequence variation was found (3.4%). Gene-dosage mutation accounted for most of the total mutations found (96.6%), and all of the heterozygous mutations were gene-dosage mutations. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD than in the controls. Conclusion: Rare genetic variant mutations of the GBA or PARK2 genes, implicated as a background for Parkinson’s disease, are also risk factors for Parkinson’s disease in the Korean population.

LSVT(Lee Silverman Voice Treatment)-BIG for LIFE 중재가 파킨슨병 환자의 신체기능, 작업수행 및 삶의 질에 미치는 영향

정선아 원광대학교 일반대학원 2025 국내박사

본 연구는 LSVT(Lee Silverman Voice Treatment)-BIG for LIFE 중재가 파 킨슨병 환자의 신체기능, 작업수행 및 삶의 질에 미치는 영향을 알아보고자 하 였다. 본 연구에서는 단일대상연구 중 ABA 중재 제거 설계를 적용하여 기초선 평 가 5회, 중재 평가 8회, 기초선 회기 5회로 진행되었다. 연구 대상자는 파킨슨병 진단을 받고 LSVT-BIG 중재를 모두 완료한 3명으로 1회에 60분, 주 2회, 4주 동안 총 8회기의 LSVT-BIG for LIFE 중재를 제공하였다. 신체기능을 평가하 기 위해 일어나 걸어가기 검사(Time Up and Go; TUG), 상자와 나무토막 검사 (Box and Block Test; BBT), 통합형 파킨슨병 평가척도(Unified Parkinson's Disease Rating Scale; UPDRS)를 사용하였다. 작업수행 평가는 캐나다작업수행 측정(Canadian Occupational Performance Measure; COPM), 삶의 질 평가는 Parkinson's Disease Questionnaire-39(PDQ-39)를 사용하였다. 연구 결과를 분 석하기 위해 반복 측정된 자료는 시각적 분석(Visual analysis)을 통해 해석하였 으며, 사전·사후 평가 결과는 비교 분석하였다. 본 연구 결과 LSVT-BIG for LIFE 중재는 파킨슨병 환자의 신체기능, 작업 수행에 긍정적인 변화를 가져왔으며 중재의 효과는 향상되거나 유지되었다. 또한 삶의 질에서는 일부 하위 항목에서 점수의 변화가 증가 또는 감소를 보였으 나 전반적으로 대부분의 항목에서 점수가 유지되었다. 본 연구를 통하여 LSVT-BIG for LIFE 중재가 파킨슨병 환자에게 있어 LSVT-BIG 종료 이후에도 지속적인 운동 수행 및 기능 유지에 효과적인 사후 관리 프로그램으로 임상적 유용성이 있다고 판단된다. 향후에는 다양한 대상자 와 확장된 중재 기간을 통해 효과를 검증하고 근거 기반의 맞춤형 중재 개발이 필요할 것으로 생각된다. 또한 본 연구는 국내에서 LSVT-BIG 중재 이후 사후 프로그램으로 LSVT-BIG for LIFE 중재를 적용한 연구로서 파킨슨병 환자를 위한 지역사회에서 건강관리를 위한 프로그램으로 활용되기를 기대한다. This study aimed to investigate the effects of LSVT(Lee Silverman Voice Treatment)-BIG for LIFE intervention on physical function, occupational performance, and quality of life in patients with Parkinson's disease. A single-subject ABA withdrawal design was employed, consisting of five baseline assessments, eight intervention sessions, and five follow-up baseline sessions. Three individuals diagnosed with Parkinson's disease participated in the study. The intervention was provided twice a week for four weeks, with each session lasting 60 minutes, totaling eight sessions of LSVT-BIG for LIFE. To evaluate physical function, the Timed Up and Go(TUG) test, Box and Block Test(BBT), and Unified Parkinson's Disease Rating Scale(UPDRS) were used. Occupational performance was assessed using the Canadian Occupational Performance Measure(COPM), and quality of life was measured using the Parkinson’s Disease Questionnaire-39(PDQ-39). For data analysis, visual analysis was applied to repeated measurements, and pre-test and post-test results were compared. The results demonstrated that the LSVT-BIG for LIFE intervention brought about positive changes in physical function and occupational performance in patients with Parkinson’s disease, with effects either maintained or improved. While some changes were observed in subdomains of quality of life with scores increasing or decreasing in certain areas most domains showed stable scores overall. Through this study, it is considered that the LSVT-BIG for LIFE intervention has clinical utility as an effective follow-up program for maintaining continuous exercise performance and functional abilities in patients with Parkinson’s disease even after the completion of LSVT-BIG. In the future, it is necessary to verify its effectiveness through a broader range of participants and an extended intervention period, as well as to develop evidence-based, tailored interventions. Furthermore, as this study applied LSVT-BIG for LIFE as a post-intervention program following LSVT-BIG in Korea, it is expected that it can be utilized as a community-based health management program for patients with Parkinson’s disease.

Narrative Medicine and TKM Music Therapy in Parkinson’s Disease

손수아 대전대학교 대학원 2025 국내석사

Objectives Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. In addition to motor symptoms such as tremor, bradykinesia, rigidity, and postural instability, patients often experience a wide range of non-motor symptoms including depression, anxiety, apathy, sleep disturbances, and autonomic dysfunction. With projections indicating that 20.6% of the South Korean population will be aged 65 or older by 2025 (Statistics Korea), there is increasing attention on Parkinson’s disease as the country transitions into an ageing society. Traditional Korean Medicine (TKM) approaches the human being from a mind–body integrative perspective, recognising disease not merely as a biological abnormality but as a holistic issue encompassing an individual’s life story. Within this framework, the present study explores the potential of music therapy—a component of traditional Korean psychological treatment—as a medium for restoring the identity and internal narrative of individual patients with Parkinson’s disease. Narrative Medicine expands the therapeutic context by centring the patient’s story, emphasising the process through which patients give meaning to their illness experiences and reconstruct their sense of self. This study adopts a narrative medicine perspective to investigate the impact of music therapy on the psychological and emotional recovery of patients with Parkinson’s disease, aiming to provide evidence for complementary and alternative approaches in PD treatment. Methods This case study involved four adult out-patients diagnosed with Parkinson’s disease. A 24-week music therapy programme was conducted, with changes before and after the intervention observed and analysed. Therapy sessions were held once a week, lasting 40–60 minutes, and included breathing exercises, singing, movement, and improvisational vocalisation. Quantitative and qualitative changes were assessed using the General Self-Efficacy Scale (GSE), EQ-5D, EQ-VAS, observational records, and patient narratives. Results Following 24 weeks of music therapy, all participants demonstrated increased scores in self-efficacy (GSE). In particular, one patient who had experienced severe panic attacks and speech inhibition continued to benefit emotionally from breathing exercises even after the programme had ended. During the later sessions, the patient began to choose songs independently and performed on stage. This behaviour reflected improved communication abilities, greater self-expression, and a renewed sense of self-esteem. For this individual, music became a means of rearticulating a personal narrative that had been disrupted by Parkinson’s disease. Conversely, one participant with severe depression experienced a worsening of symptoms post-treatment and required psychiatric care. However, her regular participation and interactions with other patients during the therapy period appeared to have a temporary positive effect on her depressive symptoms, underscoring the therapeutic value of consistent social interaction. Conclusion Music therapy offers therapeutic potential not only for improving physical function in patients with Parkinson’s disease, but also for fostering emotional recovery, enhancing self-efficacy, and reconstructing the personal narrative. The narrative medicine approach allows patients to re-interpret meaning of their illness and re-establish emotional connections with others—valuable psychosocial resources in managing Parkinson’s disease. This study suggests that music therapy may function as a therapeutic language aiding in the restoration of the self. Future clinical research should incorporate larger sample sizes and multidisciplinary collaboration to further substantiate these findings. A key limitation of this study is the small sample size, involving only four participants over the 24-week period. Moreover, as all participants concurrently received herbal medicine, acupuncture, antidepressants, and anti-Parkinsonian medications, it is difficult to attribute observed outcomes solely to the music therapy intervention. Further research involving larger cohorts is necessary to more clearly delineate the specific effects of music therapy in this context.

딥러닝 모델의 다중 작업 학습 및 확산 모델의 자기지도 학습을 이용한 파킨슨 병에서의 영상 바이오마커 개발

이유진 울산대학교 일반대학원 2025 국내박사

단순한 증상 조절이 아닌 파킨슨병의 진행을 늦추는 등 질환 자체를 치료할 수 있는 약제 개발을 위해 최근 다양한 임상 시험이 진행되고 있으며 그 대표적인 예로는 단일클론 항체가 있다. 하지만 신약의 적응증이 되는 환자들을 선별하고 약의 효과를 측정하는데 필요한 파킨슨병의 바이오마커는 아직 개발 중으로 보다 정확한 바이오마커의 신속한 개발이 필요하다. 임상의의 문진과 신경학적 진찰을 통한 파킨슨병의 진단을 뒷받침할 수 있는 검사에는 도파민 운반체 영상이 있으며 이도 파킨슨병의 바이오마커가 될 수 있는 중요한 영상 검사로 알려져 있다. 현재 임상 현장에서는 도파민 운반체 영상을 핵의학과 전문의가 정성적으로 판독하고 있으며 연구에 활용할 시 정량화해서 사용하기도 하는데 이때는 특정 관심영역을 정하고 해당 영역의 신호 세기를 평균 내어 사용한다. 반면 의료 영상에서의 인공 지능 연구가 활발히 진행되면서 자동화된 영상 분석 및 임상의가 놓치거나 파악하지 못했던 영상의 유의미한 특징을 추출하는 인공지능 모델의 성능이 점차 높아지고 있다. 본 학위 논문에서는 다양한 모델 구조와 학습 방법을 사용한 딥러닝 모델을 개발하고 이를 18F-FP-CIT PET 영상에 적용하여 파킨슨증 환자의 감별 진단, 파킨슨병 환자의 병의 진행 정도 및 예후를 예측하였으며 이에 따라 도파민 운반체 영상이 앞으로 파킨슨병의 유력한 바이오마커가 될 수 있음을 확인하였다. 본 학위 논문의 첫 번째 부분에서는 자기지도 학습 방법으로 딥러닝 모델을 개발하였으며 다양한 작업에 사용될 수 있는 범용성 모델임을 보였다. 딥러닝 모델로는 생성 모델 및 기존 영상의 일부를 보고 나머지를 예측하는 자기예측 모델을 사용하였으며 웨이블릿 변환 및 추가적인 인코더를 통한 확산 모델의 조건 적용과 같은 기술들을 적용하였다. 자기지도 학습으로 개발된 모델들은 정성적 및 정량적으로 성능을 평가하였다. 정성적으로는 잠재 공간을 시각화하고 이를 인위적으로 조정하여 변형시킨 영상을 임상적으로 해석 가능한지 확인하였고 정량적으로는 세 가지의 다른 작업에 맞게 모델의 파라미터를 튜닝하여 자기지도 학습을 하지 않은 모델과의 성능을 비교하였다. 이 세 가지 작업은 첫째, 파킨슨병 환자와 수전증 환자의 PET 영상 분류, 둘째, 파킨슨병 환자, 다계통위축 환자, 진행성 핵상마비 환자의 PET 영상 분류, 셋째, 파킨슨병 환자의 운동 증상 발현 시기 예측이다. 또한 이 세 가지 작업은 내부 데이터뿐 아니라 외부 데이터에서도 성능을 확인했는데 외부 데이터의 영상들은 모두 학습에 사용된 영상들과는 다른 PET 기계로 촬영되었으며 일부는 다른 병원의 데이터로 철저한 외부 검증을 하였다. 실험 결과 다른 딥러닝 모델에 비해서 생성 모델이 전반적으로 위 세 가지 작업에서 높은 성능을 보였으며 특히 웨이블릿 변환과 추가적인 인코더의 잠재 벡터를 순차적으로 확산 모델에 조건으로 넣어준 모델이 대부분의 작업과 데이터셋에서 높은 성능을 보였다. 본 학위 논문의 두 번째 부분에서는 첫 번째 부분과는 다르게 다중작업 학습 방법을 사용하여 범용성 보다는 하나의 작업에 특화된 딥러닝 모델을 개발하였다. 여기서는 파킨슨병의 주요한 운동 합병증 중 하나인 레보도파 유발 운동이상증의 발생 시기를 이분화 하여 예측하는 분류 모델을 만들었으며 모델이 PET 영상을 분류하면서 동시에 원본 영상을 복원하는 다중작업을 하게 된다. 또한 선행 연구에서 레보도파 유발 운동이상증과 관련 있다고 알려진 임상 변수들도 함께 모델에 넣어 모델의 성능을 올렸다. 그 외에도 학습된 모델의 설명 가능함을 확인하고 모델이 예측한 확률 값을 사용한 생존 분석을 통해 모델이 레보도파 유발 운동이상증과 관련된 영상의 특징을 효과적으로 추출하고 있는 지 확인하였다. 결론적으로 본 학위 논문은 딥러닝 모델의 성능을 다양한 작업에서 테스트하여 파킨슨병에서의 도파민 운반체 영상의 임상적 중요도를 평가하고자 하였다. 특히 파킨슨증 환자의 감별 진단뿐 아니라 파킨슨병의 진행 정도와 예후를 예측하는 다수의 작업에서 모델을 평가하였고 외부 검증을 통해 모델이 다른 환경에서 촬영한 PET 영상에도 일반화될 수 있음을 보였다. 또한 파킨슨병의 유력한 바이오마커 후보로서 도파민 운반체 영상의 가능성과 한계도 동시에 확인할 수 있었다. 본 연구를 통해 앞으로 임상 현장에서 진료에 도움을 줄 수 있는 딥러닝 모델을 개발하고자 하였고 무엇보다 모델의 결과 해석을 통해 기존에 도파민 운반체 영상에 대해 알고 있던 임상적 지식을 보다 넓히는 기회를 제공하였다. Amid ongoing trials for disease-modifying therapies, such as monoclonal antibody treatments for Parkinson's disease, there remains a pressing need for accurate biomarkers to represent the disease effectively. Dopamine transporter imaging, widely used to support clinical diagnosis based on disease course and neurological examination, is a promising candidate for an imaging biomarker in Parkinson’s disease. Previous research on dopamine transporter imaging primarily relied on human experts’ visual interpretation or quantification of striatal signal uptake patterns within predefined region-of-interests. With rapid advances in artificial intelligence, particularly in medical imaging, automated image analysis and the extraction of clinically meaningful features often overlooked by physicians have become increasingly prevalent. This thesis applies deep learning models, employing diverse architectures and training strategies, to dopamine transporter imaging with 18F-FP-CIT PET, assessing its predictive power in differential diagnosis, disease progression, and prognosis to evaluate its potential as a disease biomarker. In the first phase of this thesis, a general-purpose deep learning model trained in a self-supervised approach is proposed. Modified generative and self-prediction models, incorporating techniques like wavelet-transform input images and a semantic encoder for conditioning diffusion models, are introduced. The self-supervised pre-trained models are evaluated both qualitatively and quantitatively through latent vector visualization and manipulation, as well as fine-tuning for three downstream tasks: differential diagnosis of parkinsonism and symptom onset prediction of Parkinson’s disease using multi-center, multi- scanner external test sets. Diffusion models generally achieved top performance, with our HWDAE model, featuring a hierarchical semantic encoder and wavelet-transformed inputs, consistently demonstrating high performance in downstream tasks. In the second phase of this thesis, a different training method is proposed which concentrates on building a task-specific deep learning model using a multi-task learning approach. For the binary classification task of predicting the onset of levodopa-induced dyskinesia, a major motor complication in Parkinson’s disease, the model is trained to classify and reconstruct input images concurrently. Clinical variables associated with levodopa- induced dyskinesia are incorporated as additional inputs, enhancing model performance. Insights from explainable artificial intelligence methods and survival analysis indicate that the model effectively learned meaningful image representations with potential clinical implications. In conclusion, this thesis explores the clinical significance of dopamine transporter imaging in Parkinson’s disease by applying various deep learning methods across multiple downstream tasks, including differential diagnosis, disease progression, and prognosis, with external validation on multiple test sets. The potential of dopamine transporter imaging as a biomarker, as well as its limitations, are thoroughly examined. This work brings a step closer to implementing deep learning models in real clinical settings, while also broadening the clinical insights obtainable from dopamine transporter imaging of patients with parkinsonism. Key words: Parkinson’s disease, dopamine transporter positron emission tomography, imaging biomarker, generative model, self-supervised learning, multi-task learning.

The neurotrophic factors pathways on dopaminergic neuron and astrocyte in animal model of Parkinson’s disease

남진한 경희대학교 대학원 2014 국내박사

Part 1 The expression of human ras homolog enriched in brain with a S16H mutation [hRheb(S16H)] in adult dopaminergic (DA) neurons protects the nigrostriatal DA projection in the 6-hydroxydopamine (6-OHDA)-treated animal model of Parkinson’s disease (PD). However, the mechanism is still unclear and little is known about the induction of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) by hRheb-activated intracellular signaling pathways in adult neurons. Here, we show that transduction of nigral DA neurons with hRheb(S16H) significantly increases the levels of phospho-cAMP response element binding protein (p-CREB), GDNF and BDNF in DA neurons, and the increased levels are attenuated by rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Moreover, the protective effects of hRheb (S16H) against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity are attenuated by treatment with specific neutralizing antibodies for GDNF and BDNF. These results show that activation of hRheb/mTORC1 signaling pathway could impart to DA neurons the important ability to continuously produce GDNF and BDNF as therapeutic agents against PD. Part 2 CNTF is expressed within astrocyte of SNpc in MPP+ injected Parkinson’s animal model. And, TRPV1 exogenous agonist, capsaicin is enhanced CNTF expression within astrocyte results capsaicin prevents degeneration of nigrostriatal pathway and amphetamine-induced ipsilateral rotation behavior in MPP+ lesion Parkinson’s animal models. However, CNTF regulation mechanism is uncovered in astrocyte. Here we shown, Capsaicin regulates CNTF and mTOR downstream signal, such as p-p70S6K in mesencephalon human and rat astrocyte in vitro. And, in vivo studies, Capsaicin treated MPP+ lesion Parkinson’s animal models, p-p70S6K phosphorylation levels enhanced within astrocyte. Also, CNTF expression levels increased in CAP treated MPP+ lesion Parkinson’s animal models. These results show that capsaicin prevents degeneration of nigrostriatal pathway and amphetamine-induced rotation by TRPV1-mTOR pathway regulates CNTF in MPP+ lesion Parkinson’s animal models.

Pathogenic mechanism induced by S100A8 and S100A9, and neuroprotective effect of a novel herbmedicine, Hepad in Parkinson's disease : 파킨슨 질환에서 S100A8과 S100A9에 의한 병인기전과 Hepad의 신경보호효과

Baek, Seung Yeop Graduate School, Eulji University 2016 국내석사

S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are secreted and exert extracellular paracrine and autocrine functions. S100A8 and S100A9 affect cell death in 1-methyl-4-phenylpyridinium (MPP+) - treated dopaminergic neuronal cells. S100A8 and S100A9 induce cell death via activation of MAPK such as p38 MAPK, JNK and expression of pro-apoptotic proteins, and activation of caspase 9 and caspsase 3 in SH-SY5Y cells. S100A8 and S100A9 also trigger cell death through the Receptor for Advanced Gycation End products (RAGE) and Toll-like receptor 4 (TLR4). Injection of the 6-hydroxydopamine (6-OHDA) plus S100A8 or S100A9 causes more significant loss of tyrosine hydroxylase (TH) immunopositive cell bodies from the substantia and microgliosis than injection group of 6-OHDA in a rat model of Parkinson’s disease. These results indicate that S100A8 and S100A9 may induce neurodegenerative effect. Neuroprotective effects of a novel herb formula, Hepad was investigated on Parkinson’s disease. Dose-dependent treatment with MPP+ decreased the viability of SH-SY5Y cells, and Hepad inhibited the toxic effect of MPP+ and MPP+ plus S100A8 or S100A9. Hepad blocked the production of reactive oxygen species (ROS) induced by MPP+ in SH-SY5Y cells, and suppressed the activation of caspase 9 and caspase 3 due to MPP+. A rat model of Parkinson’s disease was generated by 6-OHDA injection into the left medial forebrain bundle (MFB) of SD rats. In amphetamine sulfate-induced rotational behavioral tests, Hepad administration attenuated circling behavior relative to the 6-OHDA-treated disease group. In addition, Hepad treatment significantly increased the TH- positive cells in the substantia nigra pars compacta (SNpc) that had decreased in response to 6-OHDA treatment. OX-6 expression, which indicates the presence of microglial cells, significantly decreased after treatment of Hepad in contrast to the 6-OHDA-treated disease group. These results indicate that Hepad may be a useful neuroprotective material for the treatment of neurodegenerative disorders such as Parkinson’s disease.