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.

Single view, video-based diagnosis of Parkinson’s Disease

Jun Seok SEO 고려대학교 대학원 2024 국내석사

Parkinson's disease is the most common neurodegenerative disorder alongside dementia. It occurs due to the destruction of dopamine-producing cells in a part of our brainstem called the substantia nigra. Parkinson's disease (PD) is a chronic illness that significantly affects the quality of life for millions of patients. Given that many patients suffer from distress once a significant portion of dopamine cells are lost, initiating symptom management as early as possible is crucial. Therefore, extensive research is underway to develop early diagnostic tools. Recently, attempts have been made to diagnose human diseases, including Parkinson's, using artificial intelligence. However, diagnosing Parkinson's disease is challenging using imaging techniques like MRI or CT, especially in its early stages. Thus, diagnosing Parkinson's requires evaluating motor and cognitive symptoms manifested by the patient, which can be assessed using scales like the Unified Parkinson's Disease Rating Scale (UPDRS). In this context, we aimed to develop an artificial intelligence diagnostic system using a 2D camera. We wanted to investigate whether a machine learning approach based on the motor symptoms of Parkinson's could distinguish between Parkinson's patients and healthy individuals. To maximize this, we introduced various scientific methods that can quantitatively evaluate gait, along with several machine learning approaches. This approach yielded promising results. Our research aimed to eliminate inter-rater variability among examiners evaluating Parkinson's disease, thereby increasing reliability and enabling rapid diagnosis through a quantitative and automated system. We attempted two studies utilizing artificial intelligence: Study 1: Gait Analysis Using a 2D Camera We proposed a system that analyzes joint data of arms and legs from frontal videos of individuals walking towards the camera using frequency-based methods. We evaluated three machine learning models on features extracted from joint dynamics using two large datasets containing a total of 300 videos, including over 50 PD patients and healthy controls. The effectiveness of these models was assessed on datasets containing patients with "mild" or "early" symptoms. By maximizing features using Short Time Auto Correlation Function (ST-ACF) and Dynamic Time Warping (DTW), we not only confirmed typical clinical expectations but also demonstrated excellent generalization performance across datasets, with an ensemble classifier achieving up to 97% accuracy. Study 2: Advanced Approach - Multifaceted Analysis Through Scientific Gait Analysis Methods We conducted a multifaceted analysis using two frameworks for estimating human posture, nine quantified gait features, and three classification methods. Additionally, we discussed the limitations of previous approaches using Dynamic Time Warping (DTW). Overall, our results highlighted the potential utility of this approach in PD diagnosis, with gait features such as Margin of Stability achieving accuracies of 98.8% and 97% for "mild" and "early" cases, respectively, emphasizing the reliability of this approach in PD diagnosis. 파킨슨병은 치매와 더불어 가장 흔한 퇴행성 신경과 질환이다. 이는 우리 뇌의 뇌간의 한 부분인 중뇌에서, 흑질이라는 부분에서의 도파민 세포들의 파괴로 일어난다. 파킨슨병(PD)은 수백만 명의 환자들의 삶의 질에 심각한 영향을 미치는 불치병이다. 도파민 세포들이 많은 부분 소실되어버린 후에 고통을 호소하는 환자들이 많기 때문에, 가능한 빨리 증상 치료를 시작하는 것이 중요하고, 이를 위해 조기 진단 도구를 개발하기 위한 많은 연구가 진행되고 있다. 이와 관련하여 최근 인간의 질병을 인공지능을 이용하여 진단하려는 시도가 일어나고 있는데, 파킨슨 병은 신경과 질환이기는 하나 초기 때에 MRI나 CT와 같은 영상학적 접근으로는 판별이 어렵다. 때문에 파킨슨병들을 진단하기 위해서는 환자에게서 외현적으로 드러나는 운동 증상과 인지 증상을 평가해야 하고, 이를 평가하는 UPDRS와 같은 척도들을 통해서 판별이 가능하다. 따라서 우리는 2D 카메라를 이용한 인공지능 진단 시스템을 개발하고자 하였다. 파킨슨병이 갖는 운동적 증상을 바탕으로 머신러닝적 접근이 파킨슨병과 정상인을 구분할 수 있는지 알아보고자 했다. 이를 극대화 하기 위해 우리는 여러가지 Machine Learning적 접근과 더불어 보행을 정량적으로 평가하는데 쓰일 수 있는 과학적인 방법들을 도입하였고, 이는 훌륭한 성과를 보여주었다. 우리가 진행했던 연구는 파킨슨병을 평가하는 검사자 간의 오차를 없애 신뢰도를 높히고, 정량화되고 자동적인 시스템을 통해 파킨슨병의 진단을 신속하게 할 수 있도록 함을 기대할 수 있다. 우리는 이에 대해 인공지능을 활용한 두 가지 연구를 시도하였다. 연구 1. 2D 카메라를 이용한 보행영상 분석 사람들이 카메라를 향해 걸어오는 전면 영상에서 양팔과 다리의 관절 데이터를 주파수 기반으로 분석하는 시스템을 제시한다. 총 300개 비디오가 포함된 두 개의 큰 데이터세트에서 50명 이상의 PD 환자와 건강한 대조군을 이용하여 관절 역학에서 추출된 주파수 기반 특징에 대해 세 가지 머신러닝 모델을 평가했다. 실험군으로 사용된 환자그룹은 "경미한" 또는 "약간의" 증상만을 가진 환자를 포함하는 두 개의 데이터셋에 대해 그 효과를 평가하였다. Short time Auto correlation function(ST-ACF)와 Dynamic Time Warping(DTW)를 이용하여 환자가 가지고 있는 feature를 극대화 하였고, 결과는 전형적인 임상적 기대(파킨슨병 환자의 다리 주파수가 느리다)를 확인할 뿐만 아니라, 앙상블 분류기의 경우 97%에 달하는 성능으로 데이터세트 간에도 뛰어난 일반화 가능성을 보여주었다. 연구 2. 발전된 방법. 보행을 분석하는 과학적 방법을 통한 다각적 분석. 우리는 사람의 자세를 추정하는 두 가지 framework와, 정량화된 서로 다른 아홉가지의 보행 특징 추출 방법, 그리고 세 가지 분류 방식을 사용하여 분류 성능을 다각적으로 분석하였다. 추가로, Dynamic Time Warping (DTW)을 사용하는 이전 접근법의 한계도 확인하고 논의하였다. 전체적으로, 우리의 결과는 안정성 한계(Margin of Stability)라는 보행 특징이 "경미한" 및 "약간의" 사례에서 각각 98.8% 및 97%의 정확도로 PD를 신뢰성 있게 식별할 수 있음을 보여주며, PD 진단에 있어 이 접근법의 잠재적 유용성을 강조하였다.

MPTP 를 이용한 파킨슨병 동물 모델에서의 케나비노이드 수용체와 바닐로이드 수용체 기능 규명

정영철 아주대학교 2010 국내박사

Parkinson’s disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibit glial activation-derived oxidative stress and inflammation, damaged blood-brain barrier (BBB), infiltrated peripheral immune cells and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Increasing evidence indicates that agonists of cannabinoid (CB) receptor and transient receptor potential vanilloid subtype 1 (TRPV1) have been shown to reduce the production of inflammatory mediators. In addition, recent studies have suggested that these receptors are implicated with the pathogenesis of neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. The purpose of this study was to investigate the role of CB receptor and TRPV1 on nigrostriatal pathway in MPTP mouse model of PD. Immunohistochemical and biochemical evidence demonstrated that MPTP injection resulted in a significant loss of DA neurons and microglial activation in the nigrostriatal pathway. Western blot analysis and double-label immunohistochemistry show that the translocation of cytosolic proteins (p47phox and Rac1) to the membrane, and p47phox expression of NADPH oxidase in microglia in the SN in vivo, indicating the activation of NADPH oxidase. Reactive oxygen species (ROS) production and oxidative damage, assessed by hydroethidine histochemistry and western blotting, were observed in the SN area in which degeneration of DA neurons occurred. In parallel, RT-PCR analysis and immunohistochemical results showed that glial activation-derived proinflammatory mediators were increased in the MPTP-treated SN. The passage of FITC-labeled albumin (FITC-LA) from blood into SN also showed the MPTP-induced damage of the brain blood barrier (BBB). Additional immunohistotochemical staining revealed peripheral immune cell (T cell, B cell, macrophage and neutorphil) infiltration in the SN and STR. However, treatment with cannabinoids (HU210 and WIN55,212-2) prevents MPTP-induced degeneration of nigrostriatal DA neurons by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS); and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. All of these neuroprotective effects were reversed by treatment with CB1 antagonist, AM251 and SR14716a, indicative of CB1 receptor mediation. Moreover, treatment with WIN55,212-2 (agonist of CB1/2) and JWH-133 (selective CB2 agonist) increased survival of DA neurons in the SN, and their fibers in the STR. This neuroprotection is accompanied by preventing of glial activation-derived proinflammatory mediators, BBB disruption and peripheral immune cell infiltration. These in vivo effects were ameliorated by treatment with CB2 antagonists AM630, suggesting direct involvement of CB2 in neuroprotection. Additional study demonstrated that treatment with capsaicin (CAP), TRPV1 agonist, also prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels and improved motor function. This neuroprotection afforded by CAP was associated with NADPH oxidase-derived ROS production, reduced expression of pro-inflammatory cytokines by activated microglia. This neuroprotective effects were reversed by treatment with TRPV1 antagonist capsazepine (CZP) and iodo-resinoferatoxin (I-RTX), indicative of TRPV1 receptor mediation. Collectively, these results suggest that cannabinoid and vanilloid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation-derived oxidative stress and proinflammatory mediators, BBB leakage and peripheral immune cell infiltration.

파킨슨병 환자의 간신(肝腎) 변증 임상 특성 및 치료 유효성 분석: 클러스터 기반 증상 군집 분석, 체계적 문헌고찰 및 전향적 관찰연구

조혜연 과학기술연합대학원대학교 한국한의학연구원(KIOM) 2026 국내박사

본 학위 논문은 파킨슨병(PD)의 한의학적 진단 체계인 변증 (Syndrome Differentiation)의 특성 및 유효성을 탐구하고, 특히 간신(肝腎) 변증을 중심으로 그 임상적 유의성과 치료적 가치를 체계적으로 분석하였다. 본 연구는 문헌베이스로 데이터 클러스터링, 체계적 문헌 고찰, 전향적 관찰 연구를 활용해 다각적으로 접근하여, 변증 기반의 진단 체계가 파킨슨병의 개인별 맞춤형 관리에 기여할 수 있음을 규명하고자 한다. 제2장에서는 군집 분석(Clustering Analysis)을 활용하여 파킨슨병 증상에 대한 데이터 기반의 새로운 분류를 제시하였다. 분석 결과, 총 4가지의 하위 변증 유형이 도출되었다: 유형 0(기양허), 유형 1(어혈을 포함한 실증), 그리고 유형 2(간신음허). 특히 유형 2는 UPDRS 점수가 가장 높고 유병 기간이 길어, 병리적으로 가장 심화된 단계를 나타냈다. 이는 간신음허를 파킨슨병의 핵심적인 진행 패턴으로 보고한 기존 문헌들을 실증적으로 뒷받침하는 결과이다. 제3장에서는 앞선 분류를 바탕으로 간신음허형 파킨슨병 환자에 대한 한약 치료의 효과를 체계적으로 평가하였다. 메타분석 결과, 한약과 양방 표준 치료의 병용 요법은 단독 요법에 비해 유의미한 임상적 이점을 보였다. 특히 PaNing Tang은 운동 및 비운동 기능 개선에서, ZuoGui Wan은 일상생활 수행 능력 개선에서 가장 높은 유효성을 기록하였다. 이는 변증에 근거한 한약 처방이 환자의 세부 증상 영역별로 차별화된 치료 혜택을 제공할 수 있음을 시사한다. 제4장에서는 다기관 전향적 관찰 연구를 통해 기존 연구들의 지리적 편향성 문제를 보완하였다. 본 연구 결과, 오장 변증과 파킨슨병 중증도 사이의 단계별 상관관계가 확인되었다. 특히 간(肝)계통의 변증 이상은 질병의 초기 단계에서 더욱 두드러지게 나타났으며, 이는 일상생활의 운동 기능 저하 및 신체적 부담과 유의한 상관관계를 보였다. 이러한 결과는 간 관련 병리 기전이 파킨슨병의 초기 임상 양상에서 핵심적인 역할을 수행함을 시사하며, 질병 초기 경과에 맞춘 정교하고 개인 맞춤형 진단 전략을 수립하는 데 중요한 근거를 제공한다. 결론적으로, 본 연구는 파킨슨병 관리에서 한의 변증이 갖는 임상적 가치를 종합적으로 입증하였다. 특히 초기 간계 중심의 기능 장애를 제시함으로써, 보다 정교한 진단 및 치료 전략을 구축하였다. 본 논문은 향후 파킨슨병의 표준화된 변증 체계 수립과 환자 개개인에게 최적화된 통합 의료 모델을 마련하는 데 중요한 학술적 토대가 될 것이다. This dissertation explores the clinical significance and therapeutic potential of syndrome differentiation (SD), with a specific focus on the Liver–Kidney pattern, in patients with Parkinson’s disease (PD). Utilizing a multidisciplinary approach—comprising clustering analysis, structured data synthesis, and systematic evaluation and prospective observation—this study elucidates how SD can serve as a robust framework for personalized PD management. Chapter 2 presents a data-driven classification of PD symptoms using clustering analysis. Four distinct SD subtypes were identified: subtype 0 (Qi/Yang Deficiency), subtype 1 (excess patterns, including Blood Stasis), and subtype 2 (Liver–Kidney Yin Deficiency). Subtype 2 had the most advanced pathological features, characterized by significantly higher Unified Parkinson’s Disease Rating Scale (UPDRS) scores and longer disease duration. These findings validate the reports in traditional literature, confirming that Liver– Kidney Yin Deficiency is a predominant and critical pattern associated with disease progression. Building upon this classification, Chapter 3 systematically evaluates the efficacy of herbal medicine targeting the Liver–Kidney Deficiency pattern. Pairwise and network meta- analyses have demonstrated that herbal medicine, when integrated with conventional Western medicine, provides superior clinical benefits over monotherapy. PaNing Tang was the most likely to offer benefits for non-motor and motor functions (UPDRS Parts I and III), whereas ZuoGui Wan was the most effective at improving daily living activities (UPDRS Part II). These suggest that SD-guided interventions offer domain-specific therapeutic advantages. Chapter 4 extends these investigations through a multicenter prospective observational study involving a non-Chinese population and addresses previous geographical biases. This study revealed a stage-specific association between five visceral patterns and disease severity. Liver pattern abnormalities were more severe during earlier stages of the disease and were significantly associated with functional burdens and impairments of daily motor activities. These findings suggest that liver-related pathological mechanisms predominantly underlie the initial clinical manifestations of PD and offer a nuanced framework for personalized management strategies focused on the early disease trajectory. In conclusion, this study provides comprehensive evidence for the clinical utility of SD in PD. By characterizing liver-dominant functional impairment during the early-to-mid stages of PD within 7 years of onset, this dissertation provides a sophisticated diagnostic- therapeutic model. These findings lay a critical foundation for future standardized SD frameworks and culturally tailored integrative care strategies to optimize the outcomes for patients with PD globally.