Risk and Modifying factors in Fronto Temporal Dementia

额颞叶痴呆的风险和改变因素

• 批准号: MR/L501542/1
• 负责人: John Hardy
• 金额: $ 58.81万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL501542%2F1
• 关键词: Risk; Modifying; factors; Fronto; Temporal

Fronto Temporal Dementia (FTD) is a devastating pre-senile dementia characterized by the progressivedeterioration of the frontal lobe and changes in social and personal behaviour and blunting of emotions.Up to 40% of cases have a positive family history and this has been the key to the remarkable progressin our understanding of the molecular basis of FTD. Seven genes have been identified of which MAPT, GRN and C9Orf72 explain >50% of familial cases, but how these different genes lead to a very similar clinical phenotype is unknown. There is no cure for FTD and success of therapy will depend on whether a single therapy can be applied to all patients or if specific approaches are needed for the distinct genetic, clinical and pathological subgroups. Therefore it is essential to identify all major genetic and environmental risk and modifying factors in the pathogenesis of the disease.We will use existing genetic and pathological knowledge as a starting point to decode affectedprocesses and pathways in different groups of patients with FTD using a multi level approach based on genetic and "omics" data from patients and corresponding animal and cellular models. The biological significance of identified networks will be validated in our cellular and animal models and will pinpoint potential pathomechanisms that are specific to a single FTD-subtype or common to all forms. The results will be utilized to improve the quality of our predictions towards targeted intervention.

额颞叶痴呆 (FTD) 是一种毁灭性的老年前痴呆症，其特征是额叶进行性恶化、社会和个人行为改变以及情绪迟钝。高达 40% 的病例有阳性家族史，这是我们在理解 FTD 分子基础方面取得显着进展的关键。已鉴定出 7 个基因，其中 MAPT、GRN 和 C9Orf72 解释了 > 50% 的家族病例，但这些不同的基因如何导致非常相似的临床表型尚不清楚。 FTD 无法治愈，治疗的成功将取决于是否可以将单一疗法应用于所有患者，或者是否需要针对不同的遗传、临床和病理亚组采取特定的方法。因此，有必要确定疾病发病机制中的所有主要遗传和环境风险以及改变因素。我们将使用现有的遗传和病理知识作为起点，使用基于患者遗传和“组学”数据以及相应动物和细胞模型的多层次方法，解码不同 FTD 患者群体中受影响的过程和途径。已识别网络的生物学意义将在我们的细胞和动物模型中得到验证，并将查明单一 FTD 亚型特有的或所有形式共有的潜在病理机制。结果将用于提高我们对有针对性的干预的预测质量。

项目成果

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease

• DOI: 10.1371/journal.pone.0218111
• 发表时间: 2019-07-08
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Baker, Emily;Sims, Rebecca;Escott-Price, Valentina
• 通讯作者: Escott-Price, Valentina

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

• DOI: 10.1038/nn.4398
• 发表时间: 2016-12
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Adams HH;Hibar DP;Chouraki V;Stein JL;Nyquist PA;Rentería ME;Trompet S;Arias-Vasquez A;Seshadri S;Desrivières S;Beecham AH;Jahanshad N;Wittfeld K;Van der Lee SJ;Abramovic L;Alhusaini S;Amin N;Andersson M;Arfanakis K;Aribisala BS;Armstrong NJ;Athanasiu L;Axelsson T;Beiser A;Bernard M;Bis JC;Blanken LM;Blanton SH;Bohlken MM;Boks MP;Bralten J;Brickman AM;Carmichael O;Chakravarty MM;Chauhan G;Chen Q;Ching CR;Cuellar-Partida G;Braber AD;Doan NT;Ehrlich S;Filippi I;Ge T;Giddaluru S;Goldman AL;Gottesman RF;Greven CU;Grimm O;Griswold ME;Guadalupe T;Hass J;Haukvik UK;Hilal S;Hofer E;Hoehn D;Holmes AJ;Hoogman M;Janowitz D;Jia T;Kasperaviciute D;Kim S;Klein M;Kraemer B;Lee PH;Liao J;Liewald DC;Lopez LM;Luciano M;Macare C;Marquand A;Matarin M;Mather KA;Mattheisen M;Mazoyer B;McKay DR;McWhirter R;Milaneschi Y;Mirza-Schreiber N;Muetzel RL;Maniega SM;Nho K;Nugent AC;Loohuis LM;Oosterlaan J;Papmeyer M;Pappa I;Pirpamer L;Pudas S;Pütz B;Rajan KB;Ramasamy A;Richards JS;Risacher SL;Roiz-Santiañez R;Rommelse N;Rose EJ;Royle NA;Rundek T;Sämann PG;Satizabal CL;Schmaal L;Schork AJ;Shen L;Shin J;Shumskaya E;Smith AV;Sprooten E;Strike LT;Teumer A;Thomson R;Tordesillas-Gutierrez D;Toro R;Trabzuni D;Vaidya D;Van der Grond J;Van der Meer D;Van Donkelaar MM;Van Eijk KR;Van Erp TG;Van Rooij D;Walton E;Westlye LT;Whelan CD;Windham BG;Winkler AM;Woldehawariat G;Wolf C;Wolfers T;Xu B;Yanek LR;Yang J;Zijdenbos A;Zwiers MP;Agartz I;Aggarwal NT;Almasy L;Ames D;Amouyel P;Andreassen OA;Arepalli S;Assareh AA;Barral S;Bastin ME;Becker DM;Becker JT;Bennett DA;Blangero J;van Bokhoven H;Boomsma DI;Brodaty H;Brouwer RM;Brunner HG;Buckner RL;Buitelaar JK;Bulayeva KB;Cahn W;Calhoun VD;Cannon DM;Cavalleri GL;Chen C;Cheng CY;Cichon S;Cookson MR;Corvin A;Crespo-Facorro B;Curran JE;Czisch M;Dale AM;Davies GE;De Geus EJ;De Jager PL;de Zubicaray GI;Delanty N;Depondt C;DeStefano AL;Dillman A;Djurovic S;Donohoe G;Drevets WC;Duggirala R;Dyer TD;Erk S;Espeseth T;Evans DA;Fedko IO;Fernández G;Ferrucci L;Fisher SE;Fleischman DA;Ford I;Foroud TM;Fox PT;Francks C;Fukunaga M;Gibbs JR;Glahn DC;Gollub RL;Göring HH;Grabe HJ;Green RC;Gruber O;Gudnason V;Guelfi S;Hansell NK;Hardy J;Hartman CA;Hashimoto R;Hegenscheid K;Heinz A;Le Hellard S;Hernandez DG;Heslenfeld DJ;Ho BC;Hoekstra PJ;Hoffmann W;Hofman A;Holsboer F;Homuth G;Hosten N;Hottenga JJ;Hulshoff Pol HE;Ikeda M;Ikram MK;Jack CR Jr;Jenkinson M;Johnson R;Jönsson EG;Jukema JW;Kahn RS;Kanai R;Kloszewska I;Knopman DS;Kochunov P;Kwok JB;Lawrie SM;Lemaître H;Liu X;Longo DL;Longstreth WT Jr;Lopez OL;Lovestone S;Martinez O;Martinot JL;Mattay VS;McDonald C;McIntosh AM;McMahon KL;McMahon FJ;Mecocci P;Melle I;Meyer-Lindenberg A;Mohnke S;Montgomery GW;Morris DW;Mosley TH;Mühleisen TW;Müller-Myhsok B;Nalls MA;Nauck M;Nichols TE;Niessen WJ;Nöthen MM;Nyberg L;Ohi K;Olvera RL;Ophoff RA;Pandolfo M;Paus T;Pausova Z;Penninx BW;Pike GB;Potkin SG;Psaty BM;Reppermund S;Rietschel M;Roffman JL;Romanczuk-Seiferth N;Rotter JI;Ryten M;Sacco RL;Sachdev PS;Saykin AJ;Schmidt R;Schofield PR;Sigurdsson S;Simmons A;Singleton A;Sisodiya SM;Smith C;Smoller JW;Soininen H;Srikanth V;Steen VM;Stott DJ;Sussmann JE;Thalamuthu A;Tiemeier H;Toga AW;Traynor BJ;Troncoso J;Turner JA;Tzourio C;Uitterlinden AG;Hernández MC;Van der Brug M;Van der Lugt A;Van der Wee NJ;Van Duijn CM;Van Haren NE;Van T Ent D;Van Tol MJ;Vardarajan BN;Veltman DJ;Vernooij MW;Völzke H;Walter H;Wardlaw JM;Wassink TH;Weale ME;Weinberger DR;Weiner MW;Wen W;Westman E;White T;Wong TY;Wright CB;Zielke HR;Zonderman AB;Deary IJ;DeCarli C;Schmidt H;Martin NG;De Craen AJ;Wright MJ;Launer LJ;Schumann G;Fornage M;Franke B;Debette S;Medland SE;Ikram MA;Thompson PM
• 通讯作者: Thompson PM

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

• DOI: 10.1038/s41380-020-0806-5
• 发表时间: 2021-10
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Alić I;Goh PA;Murray A;Portelius E;Gkanatsiou E;Gough G;Mok KY;Koschut D;Brunmeir R;Yeap YJ;O'Brien NL;Groet J;Shao X;Havlicek S;Dunn NR;Kvartsberg H;Brinkmalm G;Hithersay R;Startin C;Hamburg S;Phillips M;Pervushin K;Turmaine M;Wallon D;Rovelet-Lecrux A;Soininen H;Volpi E;Martin JE;Foo JN;Becker DL;Rostagno A;Ghiso J;Krsnik Ž;Šimić G;Kostović I;Mitrečić D;LonDownS Consortium;Francis PT;Blennow K;Strydom A;Hardy J;Zetterberg H;Nižetić D
• 通讯作者: Nižetić D

Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

使用神经阵列的散发性早期阿尔茨海默氏病的突变分析。

• DOI: 10.1016/j.neurobiolaging.2016.09.008
• 发表时间: 2017-01
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Barber IS;Braae A;Clement N;Patel T;Guetta-Baranes T;Brookes K;Medway C;Chappell S;Guerreiro R;Bras J;Hernandez D;Singleton A;Hardy J;Mann DM;ARUK Consortium;Morgan K
• 通讯作者: Morgan K

Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.

• DOI: 10.1038/s41380-019-0410-8
• 发表时间: 2020-11
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Arber C;Toombs J;Lovejoy C;Ryan NS;Paterson RW;Willumsen N;Gkanatsiou E;Portelius E;Blennow K;Heslegrave A;Schott JM;Hardy J;Lashley T;Fox NC;Zetterberg H;Wray S
• 通讯作者: Wray S