Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation

Background/Aim: Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Patients with the MAPT R406W mutation were reported to show phenotypic heterogeneity in different ethnic backgrounds. We here report the clinical and genetic characteristics of Japanese families with the R406W mutation. Methods: We examined the clinical and neuroimaging features of 6 patients from three families with the R406W mutation. We determined the genotypes of intragenic MAPT single-nucleotide polymorphisms (SNPs) and the flanking microsatellite markers to search for a common founder. Results: The initial symptom was memory loss with the average age at onset being 54 years. Anterograde amnesia with episodic memory impairment was the predominant phenotype. Behavioral and personality changes or parkinsonism is not a prominent feature. A brain MRI study revealed marked atrophy of the medial temporal lobe. Genetic analysis of SNPs and microsatellite markers revealed that the affected members of the three families share common genotypes. Conclusion: The findings of the affected members in this study, which corroborate previously reported findings of European families, suggest that the R406W mutation may represent a phenotype of predominant anterograde amnesia in FTLD-17. Our genetic data suggest that a founder effect may account for some families with the R406W mutation

質の高いデザイン活動による学生教育と周囲への波及効果に関する実践研究

　「DESIGN SOIL」のプロジェクトの教育的な効果を明らかにすることを目的とする。また、合わせてワークショップなども開催し、実習授業などに還元できるデザイン教育の有効な方法を発見することも目指す。　2016年4月のミラノでの展示会出展を通じて、複数の作品の商品化が決定するという成果が出た。　同年11月に神戸で展示会を開催したのに合わせて、DESIGN SOILのメンバーや卒業した元メンバーが話し手として自身の体験について語るトークイベントを開催した。参加した学生の声から、学生が直接現地の空気に触れ、自身の言葉で周りの学生に伝えることが最もリアリティのあることとして強く響くということが確認できた。　博物館見学をデザインと直結させるワークショップを通して、デザイン実習などにも応用できる手法を発見できた。　メンバーへのヒアリングから、DESIGN SOILの活動、海外での展示会出展が、参加学生や周囲の学生にも強い刺激を与えることができており、良い影響が循環してきていることが確認できた。It aims to clarify the educational effect of "DESIGN SOIL" project. In addition, we also hold workshops and aim to discover effective ways of design education that can be returned to practical lessons. Through the exhibition in Milan in April, several works were selected as candidates for commercialization. In conjunction with holding an exhibition in Kobe in November, members of DESIGN SOIL and former members who graduated held a talk event talking about their own experiences. It was confirmed that the words by students who exhibited in the Milan is effective as the most realistic thing for the surrounding students. Through a workshop linking the museum tour with design practice, I was able to find a method applicable to design practice etc. From the hearing to the members, the activities of DESIGN SOIL and the participation of the exhibition abroad were able to give strong stimulus to participating students and surrounding students, and it was confirmed that good influence is circulating

大学ブランドでのデザインインキュベーションのための調査と実践

日本のデザイン教育は、学生や学生の作品を市場に結びつける段階まではカバーできておらず、デザインインキュベーションという視点においてヨーロッパのデザイン先進国から大きく遅れを取っている状況にある。本研究では、デザインインキュベーションセンター立ち上げを目指して、先例を実践している大学の調査を行う。また、作品を商品として完成させるプロセスを実践し検証することを通して、教育プログラムとしての可能性も検討する。4 月のミラノでの展示会出展、6 月の神戸での展示会開催などを経て、継続的に展示会出展を含む活動を行なっていることの成果を確認できた。デザイン先進国では、国柄や文化に合った形で大学や学生が市場と繋がる取り組みを積極的に行っている。調査を通じて、日本でも独自のデザイン・インキュベーションを推進していく上で参考となる事例を確認できた。In Japanese design education, educational institutions cannot cover the stage of linking student and student work tothe market. From the viewpoint of design incubation,Japan is significantly behind the design advanced countriesof Europe.In this study, in order to set up the Design IncubationCenter, we will conduct a survey of universities thatpractice precedents.And we also consider possibilities as aneducational program through practicing and verifying theprocess of completing a work as a product.After having exhibited in Milan in April 2017 and holdingan exhibition in Kobe in June, We confirmed the result ofcontinuing activities including participation in theexhibition.In advanced countries in the design, universities andstudents are actively engaged in activities linked to themarket in a way that suits nationalities and cultures.Through the survey, we have confirmed cases that serve asreference for promoting unique design incubation in Japan

デザインチームの活動と展示会出展を通したデザイン教育の実践研究

　”Design Soil”の活動に参加したメンバーへのヒアリングを通して、1. 厳しい批評が学生を成長させる、2. チームでの実践的な経験が学生を成長させるという仮説を検証した。　仮説1. について、「厳しい批評で慢心が打ち砕かれたことと、それがあったからこそポジティブな反応が心から嬉しく、自分に自信が持てたこと、両方を経験できたことで成長できた」等の意見があり、厳しい批評をされる場に挑んだからこそ成長ができたということが確認できた。　仮説2. に関して、作品を出展した学生からは「出展できないことが決まった友達が、自分の制作を手伝ってくれたり、チーム運営に徹してくれている姿を見て力が湧いた、絶対にいいものを作るという強い意志を持てた」という意見が、出展ができなかった学生からは「ひとりであれば、出展できないと決まった時点で終わるが、チームだからその先があり、能力だけでなく人間的にも成長できた」という意見があり、チームでの活動が学生の成長に大きく関わっていることが確認できた。Through interviewing students who took part in activities of Design Soil, I verified hypotheses that 1. Good criticism makes students grow bigger, 2. Hands-on learning experience as a member of a team makes students grow bigger. Regarding hypothesis 1, some students said “My pride has dented by good criticism, and this is why I was really glad of positive reviews, and then I become convincing to myself. I had been able to grow by those both experiences.”Those cases prove the hypothesis 1. Regarding hypothesis 2, some students who exhibited their own work said “member who has rejected gave a hand to help me or worked hard for the team in their own way, its made me energetic. And it made me have a strong will to complete my work for them.” And some students who did not exhibited said “If I was individual, my challenge was ended when I was rejected. But if I was in a team, it iscontinue. I have deeply grown in faculty and as a person.”.Thus, it is confirmed that team activities influence a student’s development

APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

11 páginas, 4 figuras, 2 tablas. Datasets en su material suplementario. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2302720120/-/DCSupplemental.Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.Peer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues