臨床連携委員会企画シンポジウム「認知症・変性疾患研究の最前線：患者から科学する」
Committee-Organized Symposium |
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| 2020/9/11 9:05～9:30 Zoom B
CS2-01
レム睡眠行動異常症の前向きコホート研究によるパーキンソン病発症前バイオマーカーの探索：J-PPMI
Japan Parkinson Progressive Marker Initiative (J-PPMI): a prospective cohort study for REM sleep behavior disorder to identify prodromal biomarkers for Parkinson's disease
*髙橋 祐二1
1. 国立精神・神経医療研究センター病院 脳神経内科
*Yuji Takahashi1
1. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry
Parkinson's disease (PD) is one of the neurodegenerative diseases characterized by rigidity, bradykinesia, tremor and later on postural instability as cardinal extrapyramidal symptoms. The pathological hallmark is Lewy bodies in which a-synclein is the main constituent. PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are termed as a-synucleinopathies because of pathological deposition of a-synclein. Accumulating evidence has elucidated that REM sleep behavioral disorder (RBD) has high conversion rate to a-synucleinopathies and the underpinning mechanism of the disease progression is considered as propagation of the deposition of a-synclein.
Many therapeutics have been proved to be effective in alleviating the symptoms and improving quality of life of patient with PD. However, these therapeutics become less effective and tend to cause various complications in the advanced stage, and cannot prevent or delay the degeneration process itself. Thus, the development of disease-modifying therapies (DMTs) has been eagerly awaited.
Recent development of researches on PD has unraveled a wide variety of potential candidates for DMTs. Early diagnosis plays a critical role in maximizing their effects. Moreover, surrogate markers are the key to evaluate the effects efficiently and cost-effectively, leading to successful clinical trials for DMTs. Therefore, it is imperative to establish early-stage or prodromal biomarkers for PD.
To achieve this goal, we have launched Japan Parkinson Progressive Marker Initiative (J-PPMI) in 2015. J-PPMI has focused on RBD as an ideal prospective cohort for prodromal PD. In this symposium, we would like to demonstrate the current attainment of J-PPMI and provide the perspectives to establish prodromal biomarkers for PD.
| | 2020/9/11 9:30～9:50 Zoom B
CS2-02
認知症の臨床・病理連関
Clinical/pathological association of dementia
*齊藤 祐子1
1. 東京都健康長寿医療センター研究所 神経病理学
*Yuko Saito1
1. Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology
Although I started out as a clinical neurologist, I became interested in learning from the clinical diagnosis, and eventually the final pathological diagnosis of dementia and degenerative diseases, which are often difficult to cure. Under the project of utilizing the clinical history, clinical symptoms, images, biomarkers and pathology in a large number of cases in an actual clinical setting, it is possible to carry out earlier, accurate, and accurate treatments for the radical treatment in the future. The aim has been to make various clinical diagnoses. In addition to that, the system of brain bank was established, and in addition to returning to clinical practice, through joint research with researchers, it has also played a role of bridging the path to elucidation of disease state and drug discovery. Another Regarding the relationship between biomarkers and pathology, for example, correlations with tau PET in cases of pathologically diagnosed corticobasal degeneration were used to verify the accuracy of images and to account for REM sleep-related behavior abnormalities. Examples will be given such as learning from individual cases such as pathological estimation of lesions. A large number of studies revealed that nasal mucosal epithelium is involved in the cause of decreased olfaction in a-synucleinopathies. Various results have also been obtained in joint research with basic researchers, but drug discovery has not yet been achieved enough. Research using the human brain is indispensable for elucidating the pathophysiology of human diseases and drug discovery, but it seems that few researchers in Japan are particularly undertaking research using the human brain. In the future, I would like to play a further role in bridging clinical/pathological and basic research.
| | 2020/9/11 9:50～10:15 Zoom B
CS2-03
認知症の血液バイオマーカー
Blood biomarkers for dementia
*工藤 喬1、赤嶺 祥真1、柳田 寛太1、丸谷 典子1、金山 大祐1
1. 大阪大学大学院医学研究科 健康精神医学
*Takashi Kudo1, Shoshin Akamine1, Kanta Yanagida1, Noriko Marutani1, Daisuke Kanayama1
1. Department of Mental Health Promotion, Osaka University Graduate School of Medicine
Establishing biomarkers for dementia is essential for its diagnosis, stratification, or evaluation of drug discovery. Conventionally, analysis of cerebrospinal fluid proteins and PET of amyloid or tau have been performed as biomarkers for dementia. However, because such biomarkers are invasive or expensive, establishment of simple and inexpensive blood biomarkers is expected.
Recently, it has become possible to quantify a minute amount of protein in blood using a digital ELISA manufactured by Quanterix. In particular, neurofilament L (NFL) is being established as a biomarker for dementia as an index of neurological disorders. We also show the possibility that preclinical cognitive impairment can be detected by blood NFL in elderly diabetic patients. Since blood NFL has no disease specificity even though it can show the degree of neuropathy, similar quantification of tau and Aβ40/42 in blood has been tried. However, it is highly possible that these quantifications were those that leaked from nerve cells into plasma, and it is considered that they do not reflect real changes in nerve cells.
Exosomes released from various cells are present in blood, and their internal environment is believed to reflect that of the original cells. It is expected that nerve-derived exosomes (NDE) are present in the blood. Since NDE is covered with a membrane similar to the cell membrane of nerve cells, NDE can be collected by immunoprecipitation by targeting a membrane-specific molecule. We performed proteomics of NDE membrane, identified NDE-specific membrane protein X (MPX), and succeeded in collecting NDE using an antibody against MPX. It is considered that the NDE can be used as a new biomarker for dementia, which reflects the changes in neuronal cells of dementia.
| | 2020/9/11 10:15～10:35 Zoom B
CS2-04
Misfolded protein amplification technique; a significant innovations to develop biomarkers and therapeutics
*池中 建介1、Aguirre Cesar1、望月 秀樹1
1. 大阪大学大学院医学系研究科 神経内科
*Kensuke Ikenaka1, Cesar Aguirre1, Hideki Mochizuki1
1. Department of Neurology, Osaka University Graduate school of Medicine
Protein aggregation in the central nervous cells is the key pathological features of neurodegenerative diseases. Interestingly, recent studies of disease model animals and postmortem tissues from patients revealed that those aggregated proteins are transmitted from cells to cells partially transsynaptically and partially non-transsynaptically by circulating brain interstitial fluids. Researchers have been trying to develop the techniques to detect the aggregated proteins from the patient's sample. One of the most widely studied methods is ELISA that tells us the total amount of the protein which is supposed to accumulate in the disease. The limitation of ELISA, however, is the difficulty in the specific detection of the toxic form of that protein so that usually its diagnostic ability is not quite high.
More recently, our group and others have developed the assays for specific detection of the abnormal protein from patient's sample. By using these techniques, we could specifically amplify the α-synuclein (aSyn) aggregates, the molecule responsible for the Parkinson's disease, from patients and evaluate the amount of aggregates by monitoring an amplification process. Using this technique, we could separate PD patients from controls.
Moreover, we further developed the technique that not only detect aSyn aggregates but also evaluates the characteristics of the amplified proteins, making it possible to understand the features of the aggregated proteins in patient. By this analysis, we have succeeded in detecting different strains of aSyn aggregates from PD patients and multiple system atrophy patients.
Using these techniques, we will be able to diagnose at an extremely early stage and start disease-modifying therapy before it cross the time of no return.
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