National Taiwan University Hospital
【CurriculumVitae】
Dr.Chin-HsienLingraduatedfromCollegeofMedicine,National
TaiwanUniversity.ShereceivedherPhDtrainingfromInstitute
ofMolecularBiology,AcademiaSinica,andinvestigatedthe
molecularmechanismsofLRRK2mutationsinneuronsbyusinga
Drosophilamodelsystem.Shereceivedpost-doctoralfellowship
traininginUniversityofBritishColumbia,Canada.Dr.Linisnow
aclinicalassociateprofessorinNationalTaiwanUniversity
Hospital.Heracademicinterestsincludegenetic,biomarkerand
molecularbiologystudiesofParkinson'sdisease.Sheisnowan
executivememberofTaiwanMovementDisordersSocietyanda
representativememberoftheleadershipprogramofinternational
MovementDisorderSocietyin2015.Sheisnowamemberof
educationalcommitteeoftheMovementDisorderSociety-Asian
OceanianSection.
SelectedBibliography（2017-2020）
1.Chin-HsienLin,Shieh-YuehYang,Herng-ErHorng,etal.Plasmaα -synucleinpredictscognitivedeclineinParkinson'sdisease.Journal
ofNeurology,Neurosurgery&Psychiatry2017;88:818-824.
2.Chin-HsienLin,Pei-LungChen,Chun-HweiTai,etal.Aclinicaland
geneticstudyofearly-onsetandfamilialparkinsonisminTaiwan:
anintegratedapproachcombininggenedosageanalysisandnext
generationsequencing.MovementDisorders2019;34:506-515.
3.Chin-HsienLin,Cheng-HsuanLi,Kai-ChienYang,etal.BloodNfL:
Parkinson's disease （PD） is a common neurodegenerative disease featuring progressive decline of both motor and non-motor functions. Cognitive decline is one of the most frequent and disabling non-motor symptoms. Given the likely entry of several classes of mechanism-targeted therapies, such as those targeting the propagation of α -synuclein or LRRK2 kinase inhibitors, into early human clinical trials, the identification of easily accessible biomarkers that could reflect disease severity in PD is urgently needed. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine.
In this speech, we will discuss recent advances in the development of PD biomarkers from different aspects, including CSF and plasma biomarkers. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. The combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the differential diagnosis with various Parkinsonian syndromes in the future.
1 シ ン ポ ジ ウ ム 日
シンポジウム 29
9月1日（火）10：45 ～ 12：15 第06会場(岡山コンベンションセンター2Fレセプションホール)
En
S-29-2 Updatesofliquid biomarkersanddisease-modifyingpotentialofan antiparkinsoniandruginPD
○ ShigekiArawaka
Department of Internal Medicine IV, Division of Neurology, Osaka Medical College, Japan
【CurriculumVitae】
Education:
1996 Ph.D. Yamagata University Graduate School of Medicine 1991 M.D. Yamagata University School of Medicine
Academic Positions:
2017-present Professor, Department of Internal Medicine IV, Osaka Medical College
2016-2017 Associate Professor, Department of Neurology, Hematology, Metabolism and Diabetology, Yamagata University Faculty of Medicine 2010-2016 Assistant Professor, Department of Neurology,
Hematology, Metabolism and Diabetology, Yamagata University Faculty of Medicine 1999-2002 Postdoctoral fellow, Centre for Research in
Neurodegenerative Diseases, University of Toronto (Prof. St. Geroge-Hyslop lab.)
1998-1999 Postdoctoral fellow, Department of Neuroscience, Osaka City University Medical School
(Prof. H. Mori lab.)
1997-1998 Postdoctoral fellow, Department of Molecular Biology, Tokyo Institute of Psychiatry (Dr. H. Mori lab.)
Identification of liquid biomarkers that assess the status of neurodegeneration is required for diagnosis of Parkinson's disease
（PD） and prediction of its onset and progression. Also, development of neuroprotective drugs that slow progress of motor impairments is required for treatment of PD. These issues are closely connected and become more important if the drug needs the administration in the prodromal phase for disease-modifying effects.
The process of alpha-synuclein （α-syn） aggregation is thought to associate with neurodegeneration in PD. The levels of α-syn proteins in cerebrospinal fluid （CSF） and blood are extensively investigated as a candidate biomarker. The measurements have been performed by targeting total, oligomeric and Ser129-phosphorylated （pS129） α-syn. Additionally, several studies have tested abeta42, tau, neurofilament light chain and combination of multiple biomarkers. I will summarize advance of these studies from the viewpoint of the diagnostic and prognostic values.
Then, I will talk about effects of a monoamine oxidase-B inhibitor, selegiline, on α-syn-induced neurotoxicity in vivo. We found that selegiline attenuated A53T α-syn-induced loss of nigrostriatal TH-positive neurons with suppressing the formation and propagation of striatal pS129-α-syn-positive aggregates in rat rAAV-mediated α-syn expression models. Additionally, selegiline facilitates extracellular secretion of α-syn and reduces intracellular accumulation of redundant α-syn proteins under lysosomal and proteasomal inhibitions in SH-SY5Y cells. These findings suggest that selegiline has a new therapeutic potential to attenuate α -syn-induced neurotoxicity, although there are no clinical trials clearly showing protective effects of antiparkinsonian drugs on neurodegeneration in PD. I will discuss a perspective of the disease-modifying intervention in the prodromal phase with establishment of biomarkers for early PD.
S-29-3 Animalmodelfor disease-modifying therapiesinPD
○ HodakaYamakado
Kyoto University Hospital, Japan
【CurriculumVitae】
2000 Kyoto University School of Medicine
2000- Resident in Internal medicine, Toranomon Hospital 2003- Clinical Fellow, Dept. of Neurology, Kyoto University
Hospital
2005- Graduate student, Kyoto University Graduate School of Medicine
2009- Assistant Professor, Dept. of Neurology, Kyoto University Hospital
2010. 9- Clinical Fellow, Dept. of Neurology, Takeda General Hospital
2011- Assistant Professor, Dept. of Neurology, Kyoto University Hospital
（2015.7-2017.1） Visiting Scholar, Dept. of Neurosciences, University of California, San Diego
2019- Research associate professor, Dept. of Neurology, Kyoto University Hospital
The prodromal stage of Parkinson's disease （PD）
provides an excellent opportunity for disease-modifying therapies （DMTs）, and animal models for prodromal PD are urgently needed. Genetic studies showed that the increased expression of α-synuclein （αS） is closely linked to the development of idiopathic PD. We generated BAC transgenic mice with A5 3T mutation and three risk polymorphisms for PD, and these mice expressed pathological αS accumulation and concomitant DA neuronal loss in the SNpc without locomotor dysfunction.
They also exhibited RBD-like phenotypes as well as hyposmia, and are thus considered as prodromal PD mice model. Furthermore, they are sensitive to exogenous α S fibril injection, and they exhibited around 40 % DA neuronal loss with αS aggregation in the SNpc 2 months after injection of αS fibrils into striatum. We also tried to create prodromal PD mice model following Braak hypothesis. Injection of αS fibrils into olfactory bulb resulted in wide-spread aggregate formation of αS mainly in the limbic system. In contrast, injection of fibril into the gastrointestinal tract led to transient αS aggregate formation in the lower brainstem without further upward propagation. In conclusion, SNCA BAC transgenic mice with or without αS fibril injection can be a valuable model for the preclinical studies of DMTs in PD.
1 日 シ ン ポ ジ ウ ム シンポジウム 29
9月1日（火）10：45 ～ 12：15 第06会場(岡山コンベンションセンター2Fレセプションホール)
En
Preparing for disease-modifying therapies in PD – From biomarkers, animal models to novel therapeutic approach
Chairs：CarolynSue
TheUniversityofSydney
ShigekiArawaka
DepartmentofInternalMedicineIV,Division
ofNeurology,OsakaMedicalCollege
≪Objective≫
For the realization of disease-modifying therapies （DMT）
in PD, appropriate animal models for the preclinical study and early and progression biomarkers in PD are essential. As a target of DMT much attention have been paid for mitochondria and alpha synuclein, especially. The aim of this symposium is, 1） to update recent findings in biomarkers and animal models in PD including its prodromal stage, and 2） to introduce novel therapeutic approach, focusing on mitochondria and alpha-synuclein which are the key players in idiopathic PD.
S-29-1 UpdatesofLiquid biomarkersinPD
○ Chin-HsienLin,
Chau-chungWu,
Ming-jangChiu
National Taiwan University Hospital
【CurriculumVitae】
Dr.Chin-HsienLingraduatedfromCollegeofMedicine,National
TaiwanUniversity.ShereceivedherPhDtrainingfromInstitute
ofMolecularBiology,AcademiaSinica,andinvestigatedthe
molecularmechanismsofLRRK2mutationsinneuronsbyusinga
Drosophilamodelsystem.Shereceivedpost-doctoralfellowship
traininginUniversityofBritishColumbia,Canada.Dr.Linisnow
aclinicalassociateprofessorinNationalTaiwanUniversity
Hospital.Heracademicinterestsincludegenetic,biomarkerand
molecularbiologystudiesofParkinson'sdisease.Sheisnowan
executivememberofTaiwanMovementDisordersSocietyanda
representativememberoftheleadershipprogramofinternational
MovementDisorderSocietyin2015.Sheisnowamemberof
educationalcommitteeoftheMovementDisorderSociety-Asian
OceanianSection.
SelectedBibliography（2017-2020）
1.Chin-HsienLin,Shieh-YuehYang,Herng-ErHorng,etal.Plasmaα -synucleinpredictscognitivedeclineinParkinson'sdisease.Journal
ofNeurology,Neurosurgery&Psychiatry2017;88:818-824.
2.Chin-HsienLin,Pei-LungChen,Chun-HweiTai,etal.Aclinicaland
geneticstudyofearly-onsetandfamilialparkinsonisminTaiwan:
anintegratedapproachcombininggenedosageanalysisandnext
generationsequencing.MovementDisorders2019;34:506-515.
3.Chin-HsienLin,Cheng-HsuanLi,Kai-ChienYang,etal.BloodNfL:
AbiomarkerfordiseaseseverityandprogressioninParkinson's
disease.NeurologyNeurology.2019;93（11）:e1104-e1111.
Parkinson's disease （PD） is a common neurodegenerative disease featuring progressive decline of both motor and non-motor functions. Cognitive decline is one of the most frequent and disabling non-motor symptoms. Given the likely entry of several classes of mechanism-targeted therapies, such as those targeting the propagation of α -synuclein or LRRK2 kinase inhibitors, into early human clinical trials, the identification of easily accessible biomarkers that could reflect disease severity in PD is urgently needed. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine.
In this speech, we will discuss recent advances in the development of PD biomarkers from different aspects, including CSF and plasma biomarkers. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. The combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the differential diagnosis with various Parkinsonian syndromes in the future.
1 シ ン ポ ジ ウ ム 日
9月1日（火）10：45 ～ 12：15 第06会場(岡山コンベンションセンター2Fレセプションホール)
S-29-4 Noveltherapeutic strategiestargeting mitochondria
○ CarolynM.Sue
1,21 Kolling Institute of Medical Research, Australia,
2 University of Sydney, Australia
【CurriculumVitae】
Carolyn Sue is Executive Director of the Kolling Institute of Medical Research, University of Sydney and Head of the Department of Neurogenetics at Royal North Shore Hospital and Director of the Parkinson’s Disease Centre of Excellence, Kolling Institute, University of Sydney. She was the first female adult neurologist to be promoted to Professor in Australia. Professor Sue is recognised internationally for her expertise in mitochondrial medicine and movement disorders. Her research studies investigate the role of mitochondria in neurodegeneration as it relates to mitochondrial and other neurodegenerative diseases such as Parkinson Disease.
The results of her research are translated into her clinical practice to achieve her overall goal of improving the clinical care of her patients. Professor Sue is currently Co-Chair of the Education Committee for the International Parkinson and Movement Disorder Society and is appointed to the Society’s LEAP Faculty, Task Force on Genetic Nomenclature in Movement Disorders, as well as the Scientific Program Committee. She is also President-Elect for the Movement Disorders Society of Australia and New Zealand.
Mitochondria are key organelles that are crucial for normal cellular function and energy production. Mitochondria provide the main source of cellular energy in the form of ATP. ATP is produced by the mitochondrial respiratory chain, via a process called oxidative phosphorylation.
During oxidative phosphorylation, oxygen free radicals are generated and may result in mitochondrial damage, reduced bioenergetic function and lead to "mitophagy", a process by which damaged mitochondria are selectively removed to maintain mitochondrial quality and cellular health. Mitochondrial toxins （such as Complex I inhibitors）
and loss of mitophagic proteins are causally linked to Parkinson's disease, underpinning the importance of mitochondrial function to the pathogenesis of this disorder.
Methods to preserve mitochondrial quality and function represent a promising and new therapeutic approach to providing neuroprotection to patients with Parkinson's disease.
S-29-5 Disease-modifying therapeuticstargeting alpha-synuclein
○ MasayukiNakamori
Department of Neurology, Osaka University Graduate School of Medicine, Japan
【CurriculumVitae】
Dr. Masayuki Nakamori is an Assistant Professor in the Department of Neurology at Osaka University Graduate School of Medicine.
Dr. Nakamori studied at Osaka University, receiving his M.D. in 1999. He trained in Neurology at Osaka University Hospital, Osaka Koseinenkin Hospital, and National Toneyama Hospital. He then received his Ph.D. in 2007 from Osaka University Graduate School of Medicine, for his thesis work on myotonic dystrophy. From 2007 to 2012, he did postdoctoral research in Charles Thornton's lab at the University of Rochester, where he studied trinucleotide In synucleinopathies such as Parkinson's disease （PD）, dementia with Lewy bodies （DLB）, and multiple system atrophy （MSA）, accumulation and aggregation of α-synuclein （SNCA） trigger cytotoxicity and neurodegeneration. When treating synucleinopathies, a therapy to exogenously compensate for dopamine deficiency in the brain due to the degeneration of dopaminergic neurons, has become most common.
However, the treatment is not immune to decreased drug efficacy with disease progression. In contrast, if a therapy targeting SNCA, which constitutes the essential disease condition for synucleinopathies, became available, it could be a definitive treatment that suppresses the progression of neuronal degeneration. In line with the rapid progress in nucleic acid modification techniques, a therapeutic approach that prevents the production of target proteins using nucleic acids medicine has become available.
Our group is attempting to treat PD using nucleic acid medicine targeting SNCA. We use Gamper-type antisense oligonucleotides （ASOs） that incorporate a novel nucleic acid modification, amino-bridged nucleic acids （AmNA）.
These AmNA-ASOs have the advantages of enhanced binding capacity and stability, as well as reduced toxicity.
In our previous studies, we optimized the sequence and structure of ASOs that most effectively suppresses SNCA mRNA. By administration into lateral ventricles in mouse models of PD, the ASO was efficiently delivered into mouse brains. Furthermore, the ASO suppressed the levels of SNCA in the striatum of mouse models and improved their motor symptoms. We are currently testing the efficacy and safety of the ASO in non-human primate to proceed this therapeutic approach to clinic, especially for familial PD （PARK4） that is caused by SNCA overexpression. If we can establish an SNCA suppression treatment for PARK4 using ASO, this therapy might eventually be applied to all kinds of synucleinopathies and serve as a groundbreaking disease-modifying therapy.
1 シ ン ポ ジ ウ ム 日
シンポジウム 30
9月1日（火）10：45 ～ 12：15 第07会場(岡山コンベンションセンター2F展示ホール)