Two of Ten Elderly Have Dementia When Entering Age of 70 Years Old

Life expectancy of Indonesia has increased in the few decades; it has now reached the age of 70 years. As age increases, the risk of degenerative diseases, like dementia is also increasing. As many as 60-70% of dementia cases are Alzheimer\u27s disease. However, there is only limited information on the prevalence rate of dementia in Indonesia. Early detection of dementia and knowing its prevalence rate is very important especially, since in most progressive case of dementia, including the Alzheimer\u27s disease, there is no known cure

Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.

Background Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs.Results Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia.Conclusions This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation

Angka Prevalensi Demensia, Perlu Perhatian Kita Semua

Kurang dari empat tahun Indonesia akan memiliki struktur penduduk yang tua, yaitu persentase penduduk yang berusia 60 tahun atau lebih paling tidak 10%. Seiring dengan peningkatan jumlah penduduk lanjut usia terjadi juga peningkatan jumlah penduduk dengan penyakit degeneratif seperti demensia. Sebanyak 60-70 % demensia, merupakan demensia Alzheimer. Demensia Alzheimer (pikun) merupakan penyakit degeneratif dimana terjadinya penurunan fungsi otak yang mempengaruhi emosi, daya ingat, pengambilan keputusan, perilaku dan fungsi otak lainnya hingga mengganggu aktivitas sehari-hari. Pada saat ini belum diketahui secara pasti berapa banyak lanjut usia di Indonesia yang mengalaminya. Pengetahuan masyarakat tentang demensia Alzheimer (pikun) sebagai sebuah penyakit juga masih kecil. Sebagian besar masyarakat menganggap demensia Alzheimer (Pikun) sebagai bagian dari proses penuaan yang sifatnya alami. Di sisi lain penyakit demensia alzheimer belum ada obatnya sehingga deteksi dini sangat perlu dilakukan, termasuk angka prevalensi pada masyarakat perlu diketahui untuk mengetahui beban dari komunitas dan pelayanan kesehatan. Salah satu tujuan dari survei demensia di D I Yogyakarta yang dilakukan oleh SurveyMETER pada tahun 2016 dengan support dari Knowledge Sector Initiative DFAT adalah untuk mendapatkan prevalensi demensia. Survey ini dibangun dari hasil studi Demensia di Jakarta dan juga dari Survei Kehidupan Rumah Tangga Indonesia (SAKERTI) atau Indonesia Family Life Survey (IFLS). DI Yogyakarta merupakan provinsi dengan persentase jumlah lanjut usia terbanyak di Indonesia. Persentase lanjut usia Indonesia 15 tahun lagi terlihat di D I Yogyakarta sekarang. Angka prevalensi demensia dari survei demensia di D I Yogyakarta menunjukan nilai yang lebih tinggi dibandingkan dengan angka prevalensi pada tingkat internasional. Seberapa besar lebih tingginya tingkat prevalensi demensia pada setiap kelompok umur, tempat tinggal dan implikasinya dipaparkan dalam policy brief ini

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders

LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places

Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

ConclusionsThis is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.</p

Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

$\textbf{Background:}$ Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. $\textbf{Results:}$ Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. $\textbf{Conclusions:}$ This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.A.U. is supported by the South-East Norway Health Authorities (Helse Sor-Ost grant ID 2014040) at the Oslo University Hospital, and the Norwegian Centre for Molecular Medicine. I.G.M. is supported by funding from the Research Council of Norway (RCN), South East Norway Health Authority (SENHA) and the University of Oslo through the Centre for Molecular Medicine (Norway), which is part of the Nordic EMBL (European Molecular Biology Laboratory) partnership and also supported by Oslo University Hospitals. I.G.M. is also supported by the Norwegian Cancer Society and by EU FP7 funding. I.G.M. holds a visiting scientist position with Cancer Research UK through the Cambridge Research Institute and a Senior Visiting Research Fellowship with Cambridge University through the Department of Oncology. A.U. is funded by the SENHA at the Oslo University Hospital. V. Z. is supported by the Centre for Molecular Medicine (Norway) and together with A.W., F.B and O.A.A. supported by the Norwegian Centre of Research in Mental Disorders (NORMENT) with funding from the RCN, SENHA, Norwegian Health Association and KG Jebsen Foundation. This work was supported by the Kristian Gerhard Jebsen Foundation, Centre for Molecular Medicine Norway, Research Council of Norway (213837, 223273), South-East Norway Health Authorities (2013–123), National Institutes of Health (R01AG031224, R01EB000790 and RC2DA29475). I.G.M. and group members participate in the NIH Genetic Associations and Mechanisms in Oncology (GAME-ON): A Network of Consortia for Post-Genome Wide Association (Post-GWA) Research (prostate: 1U19CA148537-01). This work was also supported by Cancer Research UK Grant C5047/A3354. We would also like to thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now known as Prostate Cancer UK), the National Cancer Research Network UK and the National Cancer Research Institute (NCRI) UK. The ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, UK, Cancer Research UK grant number C522/A8649, Medical Research Council (UK) grant number G0500966, ID 75466 and the NCRI, UK. The epidemiological data for ProtecT were generated through funding from the Southwest National Health Service Research and Development