TOP ＞ シンポジウム（Symposium）

Symposium Prodromal PD -bench to bedside- シンポジウム 前駆期パーキンソン病ーbench to bedsideー 7月28日（日）8:50～9:15　第1会場（朱鷺メッセ　4F　国際会議室） 4S01m-1 JPPMI-前駆期パーキンソン病のコホート研究 Noriko Nishikawa（西川 典子） 国立精神・神経セ病院 Prodromal Parkinson's disease (PD) is the period before the onset of motor symptoms. About five years before the onset of motor symptoms loss of dopamine nerve begins. Non-motor symptoms such as constipation, daytime overdose, depression, RBD, etc. appear before dopamine neuron dropout. This means that synuclein has already deposited on peripheral tissues, autonomic nerves, brain stem, and injured the site. Of these symptoms, the symptom specific to PD is RBD. RBD has a prevalence of only 0.5% in the general population, but the prevalence of RBD in PD patients is as high as about 30%. It is also known that prospective cohorts of RBD patients overseas develop a neurodegenerative disease such as PD and DLB at high rates (33.1% in 5 years, 75.7% in 10 years). Even in Japan, we launched prospective cohort study (J-PPMI) of RBD at five facilities. In J-PPMI, 109 RBD patients have been registered up to now. In this study it is diagnosed with RBD to check the REM without atonia at PSG, without parkinsonism and dementia. We conduct MDS-UPDRS semiannually and check whether there is emergence of parkinsonism etc. Every year, neurological findings, brain MRI examination, DAT-SPECT, MIBG myocardial scintigraphy, cognitive function evaluation by psychologists, and various questionnaire surveys are carried out. This study considers the regular preservation of biological samples to be an important role, and it carries blood test every six months, cerebrospinal fluid test every year, and stores specimens appropriately. I would like to show the results of the initial evaluation of J-PPMI in this session. These results can be said to be cross-sectional survey results of 109 RBD in Japan. Until now, tracking for up to three and a half years has been completed, and about 5% of the participants developed neurodegenerative diseases. It is the future goal to find out what kind of change is occurring at the time of the onset and to identify biomarkers at the PD prodrome stage. 7月28日（日）9:40～10:05　第1会場（朱鷺メッセ　4F　国際会議室） 4S01m-3 前駆期パーキンソン病の動物モデル Hodaka Yamakado（山門 穂高） 京都大院医臨床神経 The prodromal stage of Parkinson's disease (PD) provides an excellent opportunity to start disease-modifying therapies. From this perspective, animal models that recapitulate the symptoms and pathologies of prodromal PD are urgently needed. Since subjects with α-syn gene (SNCA) multiplication develop autosomal dominant familial PD and a GWAS in PD has identified SNCA as a risk gene for PD, the increased expression of α-syn is closely associated with the etiology of PD. We generated bacterial artificial chromosome (BAC) transgenic mice harboring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-syn. Furthermore, in order to enhance the pathological properties of α-syn, an A53T mutation and three risk polymorphisms for PD were inserted into transgenic SNCA construct. These A53T SNCA BAC transgenic mice expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-syn in the regions that are specifically affected in PD and/or DLB (dementia with Lewy bodies), including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behavior disorder (RBD), at as early as five months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem are positive for phosphorylated α-syn (p-α-syn). In addition, they also showed hyposmia at nine months of age, which is consistent with the significant accumulation of p-α-syn in the olfactory bulb. The DA neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal PD that showed RBD-like behavior and hyposmia without motor symptoms, and these results suggest the importance of increased α-syn expression in the initiation of PD pathology which can be a target of disease-modifying therapies for PD. 7月28日（日）9:15～9:40　第1会場（朱鷺メッセ　4F　国際会議室） 4S01m-2 パーキンソン病におけるシヌクレイン病変の進展 Koichi Wakabayashi（若林 孝一） 弘前大学医学研究科脳神経病理学講座 The histological hallmark of Parkinson disease (PD) and dementia with Lewy bodies (DLB) is neuronal alpha-synuclein aggregates called Lewy bodies and Lewy neurites. To date, more than 100 molecules have been identified in Lewy bodies, in which phosphorylated alpha-synuclein is a major constituent. PD is traditionally considered a movement disorder with lesions in the brainstem pigmented nuclei. However, accumulating evidence suggests that non-motor complications are also common in PD. Braak et al. proposed a pathological staging scheme for PD, in which early alpha-synuclein pathology is present in the dorsal vagal nucleus and in the olfactory bulb. This staging system characterizes a progression from the dorsal vagal nucleus (stage 1), through the pontine tegmentum (stage 2), into the midbrain and neostriatum (stage 3), and then the basal procencephalon and mesocortex (stage 4), and finally through the neocortex (stages 5 and 6). Braak PD stages 1-3 correspond to incidental Lewy body disease (ILBD), which is considered to represent the presymptomatic PD and/or DLB. In PD and DLB, Lewy bodies and Lewy neurites are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. In ILBD, Lewy bodies occur in the brain, spinal cord, sympathetic ganglia, visceral autonomic nervous system and skin. In addition, neuronal loss is found in the substantia nigra, striatum and heart in ILBD. Recently, Adler and Beach examined 466 whole-body autopsies from elderly subjects. They reported that olfactory bulb was the sole affected site in 52 cases and that there were no cases in which alpha-synuclein pathology was present in the peripheral nervous system, but not in the central nervous system. In conclusion, pathological process of PD targets the peripheral autonomic nervous system at the same time that lower brainstem nuclei become involved. However, olfactory bulb may be the earliest site of Lewy pathology. 7月28日（日）10:05～10:30　第1会場（朱鷺メッセ　4F　国際会議室） 4S01m-4 細胞外α-synucleinは電気活動依存性に増加する Kaoru Yamada（山田 薫），Takeshi Iwatsubo（岩坪 威） 東京大院医 The pathological aggregation of α-synuclein is a hallmark of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy collectively referred to as α-synucleinopathies.While α-synuclein aggregates intracellularly, extracellular α-synuclein also has pathological significance: it exhibits cellular toxicity, impairs synaptic transmission and initiates trans-cellular transmission of α-synuclein pathology. α-Synculein is actively released under physiological conditions, however, the primary mechanism that regulates its extracellular levels are not fully understood. Using primary neuronal culture and microdialysis in freely moving mice, we asked if neuronal/synaptic activities are involved in α-synuclein release. Herein we demonstrated that elevating neuronal activity rapidly increased, while blocking activity decreased α-synuclein release. In vivo microdialysis experiments revealed that ~70% of α-synuclein in brain interstitial fluid arises from neuronal activity-dependent pathway. Selective modulation of glutamatergic neurotransmission altered extracellular α-synuclein levels, implicating the involvement of this specific neuronal network. Enhancing synaptic vesicle release while simultaneously blocking depolarization and post-synaptic glutamate receptor activation also elicited α-synuclein release, suggesting that pre-synaptic vesicle exocytosis is a critical downstream event associated with α-synuclein release. We also found that extracellular α-synuclein exists as high molecular weight species that are distinct from its monomeric form. The present study uncovers a novel regulatory pathway associated with α-synuclein release. The dysregulation of activity-dependent release of α-synuclein might influence various pathological actions of extracellular α-synuclein including its trans-synaptic propagation.