Neuroimaging and fluid biomarkers predicting conversion and disease progression in mutation carriers of genetic frontotemporal dementia.
Projectomschrijving
Frontotemporale dementie (FTD) is een klinisch, pathologisch en genetisch heterogene neurodegeneratieve aandoening, die zich kenmerkt door veranderingen in het gedrag en de taal. In 30% van de gevallen wordt FTD veroorzaakt door een erfelijke afwijking. Familieleden van patiënten met deze erfelijke afwijking hebben daardoor 50% kans om FTD te ontwikkelen. Juist door deze personen te onderzoeken, is het mogelijk om de vroegste veranderingen in bloed en hersenvocht, op MRI-scans en bij cognitieve testen vast te leggen. Zo kan de ziekte beter worden vastgesteld en kan er ook een meer betrouwbare voorspelling worden gedaan over het begin van de ziekte.
Aanpak
In de FTD-RisCstudie volgen wij sinds 2010 een grote groep van FTD familieleden, door ieder jaar neuropsychologisch onderzoek, hersenscans (MRI), en afname van bloed en/of hersenvocht te herhalen.
Resultaten
In dit onderzoek hebben wij diverse vroege biomarkers voor FTD geïdentificeerd, die o.a. meer inzicht geven in het pathofysiologische ziekteproces, maar die ook van groot belang zijn voor de ontwikkeling van medicamenteuze behandelingen. Ze vormen een aanknopingspunt voor ziekte als klinische uitkomstmaten.
Meer informatie
- Onderzoek naar frontotemporabele dementie - interview met projectleider John van Swieten
- Dementie
Producten
Auteur: McCarthy J, Borroni B, Sanchez-Valle R, Moreno F, Laforce R Jr, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Butler C, Gerhard A, Danek A, Levin J, Otto M, Frisoni G, Ghidoni R, Sorbi S, Jiskoot LC, Seelaar H, van Swieten JC, Rohrer JD, Iturria-Medina Y, Ducharme S; GENetic Frontotemporal Dementia Initiative (GENFI).
Magazine: Human Brain Mapping
Auteur: Lize C. Jiskoot1,2,3, Martina Bocchetta2 , Jennifer M. Nicholas2,4 , David M. Cash2,5, David Thomas2,5, Marc Modat2,5, Sebastien Ourselin2,5, Serge A.R.B. Rombouts3,6,7, Elise G.P. Dopper1 , Lieke H. Meeter1 , Jessica L. Panman1,3, Rick van Minkelen8 , Emma L. van der Ende1,3, Laura Donker Kaat1,9, Yolande A.L. Pijnenburg10, Barbara Borroni11, Daniela Galimberti12, Mario Masellis13, Maria Carmela Tartaglia14, James Rowe15, Caroline Graff16, Fabrizio Tagliavini17, Giovanni B. Frisoni18,19, Robert
Magazine: Annals of Clinical and Translational Neurology
Auteur: Young AL, Bocchetta M, Russell LL, Convery RS, Peakman G, Todd E, Cash DM, Greaves CV, van Swieten J, Jiskoot L, Seelaar H, Moreno F, Sanchez-Valle R, Borroni B, Laforce R Jr, Masellis M, Tartaglia MC, Graff C, Galimberti D, Rowe JB, Finger E, Synofzik M, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler C, Gerhard A, Levin J, Danek A, Otto M, Sorbi S, Williams SCR, Alexander DC, Rohrer JD; Genetic FTD Initiative (GENFI).
Magazine: Neurology
Auteur: Bergström S, Öijerstedt L, Remnestål J, Olofsson J, Ullgren A, Seelaar H, van Swieten JC, Synofzik M, Sanchez-Valle R, Moreno F, Finger E, Masellis M, Tartaglia C, Vandenberghe R, Laforce R, Galimberti D, Borroni B, Butler CR, Gerhard A, Ducharme S, Rohrer JD, Månberg A, Graff C, Nilsson P; Genetic Frontotemporal Dementia Initiative (GENFI).
Magazine: Molecular neurodegeneration
Auteur: van der Ende EL, Bron EE, Poos JM, Jiskoot LC, Panman JL, Papma JM, Meeter LH, Dopper EGP, Wilke C, Synofzik M, Heller C, Swift IJ, Sogorb-Esteve A, Bouzigues A, Borroni B, Sanchez-Valle R, Moreno F, Graff C, Laforce R, Galimberti D, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, Rowe JB, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Pijnenburg YAL, Sorbi S, Zetterberg H, Niessen WJ, Rohrer JD, Klein S, van Swieten JC, Venkatraghavan V,
Magazine: Brain
Auteur: Panman JL, Venkatraghavan V, van der Ende EL, Steketee RME, Jiskoot LC, Poos JM, Dopper EGP, Meeter LHH, Donker Kaat L, Rombouts SARB, Vernooij MW, Kievit AJA, Premi E, Cosseddu M, Bonomi E, Olives J, Rohrer JD, Sánchez-Valle R, Borroni B, Bron EE, Van Swieten JC, Papma JM, Klein S; GENFI consortium investigators.
Magazine: Journal of Neurology, Neurosurgery and Psychiatry
Auteur: van der Ende EL, Jackson JL, White A, Seelaar H, van Blitterswijk M, Van Swieten JC.
Magazine: Journal of Neurology, Neurosurgery and Psychiatry
Auteur: van den Berg E, Poos JM, Jiskoot LC, Montagne B, Kessels RPC, Franzen S, van Hemmen J, Eikelboom WS, Heijboer EGC, de Kriek J, van der Vlist A, de Jong FJ, van Swieten JC, Seelaar H, Papma JM.
Magazine: Assessment
Auteur: Franklin HD, Russell LL, Peakman G, Greaves CV, Bocchetta M, Nicholas J, Poos J, Convery RS, Cash DM, van Swieten J, Jiskoot L, Moreno F, Sanchez-Valle R, Borroni B, Laforce R Jr, Masellis M, Tartaglia MC, Graff C, Galimberti D, Rowe JB, Finger E, Synofzik M, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler C, Gerhard A, Levin J, Danek A, Otto M, Sorbi S, Le Ber I, Pasquier F, Rohrer JD; Genetic FTD Initiative, GENFI.
Magazine: Alzheimer's research & therapy
Auteur: Poos JM, van den Berg E, Visch-Brink E, Eikelboom WS, Franzen S, van Hemmen J, Pijnenburg YAL, Satoer D, Dopper EGP, van Swieten JC, Papma JM, Seelaar H, Jiskoot LC
Magazine: Archives of Neurology
Auteur: Shafiei G, Bazinet V, Dadar M, Manera AL, Collins DL, Dagher A, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Butler C, Gerhard A, Danek A, Levin J, Otto M, Sorbi S, Jiskoot LC, Seelaar H, van Swieten JC, Rohrer JD, Misic B, Ducharme S; Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI); GENetic Frontotemporal dementia Initiative (GENFI).
Magazine: Brain
Auteur: Poos JM, Moore KM, Nicholas J, Russell LL, Peakman G, Convery RS, Jiskoot LC, van der Ende E, van den Berg E, Papma JM, Seelaar H, Pijnenburg YAL, Moreno F, Sanchez-Valle R, Borroni B, Laforce R, Masellis M, Tartaglia C, Graff C, Galimberti D, Rowe JB, Finger E, Synofzik M, Vandenberghe R, de Mendonça A, Tiraboschi P, Santana I, Ducharme S, Butler C, Gerhard A, Levin J, Danek A, Otto M, Le Ber I, Pasquier F, van Swieten JC, Rohrer JD; Genetic FTD Initiative (GENFI).
Magazine: Alzheimer's research & therapy
Auteur: Rojas JC, Wang P, Staffaroni AM, Heller C, Cobigo Y, Wolf A, Goh SM, Ljubenkov PA, Heuer HW, Fong JC, Taylor JB, Veras E, Song L, Jeromin A, Hanlon D, Yu L, Khinikar A, Sivasankaran R, Kieloch A, Valentin MA, Karydas AM, Mitic LL, Pearlman R, Kornak J, Kramer JH, Miller BL, Kantarci K, Knopman DS, Graff-Radford N, Petrucelli L, Rademakers R, Irwin DJ, Grossman M, Ramos EM, Coppola G, Mendez MF, Bordelon Y, Dickerson BC, Ghoshal N, Huey ED, Mackenzie IR, Appleby BS, Domoto-Reilly K, Hsiung GR, To
Magazine: Neurology
Auteur: J. M. Poos1,2 · L. C. Jiskoot1,3 · S. M. J. Leijdesdorff4 · H. Seelaar1 · J. L. Panman1,2 · E. L. van der Ende1 · M. O. Mol1 · L. H. H. Meeter1 · Y. A. L. Pijnenburg5 · L. Donker Kaat1,6 · F. J. de Jong1 · J. C. van Swieten1 · J. M. Papma1 · E. van den Berg1
Magazine: Journal of Neurology
Auteur: Premi E, Costa T, Gazzina S, Benussi A, Cauda F, Gasparotti R, Archetti S, Alberici A, van Swieten JC, Sanchez-Valle R, Moreno F, Santana I, Laforce R, Ducharme S, Graff C, Galimberti D, Masellis M, Tartaglia C, Rowe JB, Finger E, Tagliavini F, de Mendonça A, Vandenberghe R, Gerhard A, Butler CR, Danek A, Synofzik M, Levin J, Otto M, Ghidoni R, Frisoni G, Sorbi S, Peakman G, Todd E, Bocchetta M, Rohrer JD, Borroni B; GENFI Consortium Members.
Magazine: Journal of Alzheimer's disease
Auteur: Emma L. van der Ende1 *, Lieke H. Meeter1 *, Christoph Stingl2 , Jeroen G. J. van Rooij1,3, Marcel P. Stoop2 , Diana A. T. Nijholt2 , Raquel Sanchez-Valle4 , Caroline Graff5,6, Linn Oijerstedt € 5,6, Murray Grossman7 , Corey McMillan7 , Yolande A. L. Pijnenburg8 , Robert Laforce Jr9 , Giuliano Binetti10,11, Luisa Benussi10, Roberta Ghidoni10, Theo M. Luider2 , Harro Seelaar1 & John C. van Swieten1
Magazine: Annals of Clinical and Translational Neurology
Auteur: E. van den Berg1 , J.M. Poos1, L.C. Jiskoot1,2, L.M. Heijnen1, S. Franzen1 , R.M.E. Steketee3, R. Meijboom3,4,5, F.J. de Jong1, H. Seelaar1, J.C. van Swieten1 and J.M. Papma1
Magazine: Journal of the International Neuropsychological Society
Auteur: van der Ende EL, Morenas-Rodriguez E, McMillan C, Grossman M, Irwin D, Sanchez-Valle R, Graff C, Vandenberghe R, Pijnenburg YAL, Laforce R, Ber IL, Lleo A, Haass C, Suarez-Calvet M, van Swieten JC, Seelaar H
Magazine: Neurobiology of Aging
Auteur: Poos, J.M., van den Berg, E., Papma, J.M., van der Tholen, F.C., Seelaar, H., Donker Kaat, L., Kievit, J.A., Tibben, A., van Swieten, J.C., Jiskoot, L.C.
Magazine: Frontiers in Psychiatry
Auteur: Poos, J.M., Macdougall, A., van den Berg, E., Jiskoot, L.C., Papma, J.M., van der Ende, E., Seelaar, H., Russell, L.L., Peakman, G., Convery R.S, Pijnenburg, Y.A.L, Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Doré, M.C., Masellis, M., Tartaglia, C., Graff, C., Galimberti, D, Rowe, J.B., Finger, E., Synofzik, M., Vandenberghe, R., de Mendonça, A., Tiraboschi, P., Santana, I., Ducharme, S., Butler, C., Gerhard, A., Levin, J., Danek, A., Otto, M., Le Ber, I., Pasquier, F., van Swiete
Magazine: Neurology
Auteur: Author links open overlay panelEmma Lvan der EndeMDaLieke HMeeterMDaJackie MPoosMScaJessica LPanmanMScabLize CJiskootPhDacElise G PDopperMDaJanne MPapmaPhDaFrank Jande JongMDaInge M WVerberkMScdProfCharlotteTeunissenPhDdProfDimitrisRizopoulosPhDeCarolinHellerMSccRhian SConveryMSccKatrina MMooreBSccMartinaBocchettaPhDcMollieNeasonMSccDavid MCashPhDcBarbaraBorroniMDfDanielaGalimbertiPhDghRaquelSanchez-ValleMDiRobertLaforceJrMDjFerminMorenoMDkProfMatthisSynofzikMDlmProfCarolineGraffMDnoMarioMaselli
Magazine: The Lancet Neurology
Auteur: Lize C Jiskoot, Jessica L Panman, Lieke H Meeter, Elise G P Dopper, Laura Donker Kaat, Sanne Franzen, Emma L van der Ende, Rick van Minkelen, Serge A R B Rombouts, Janne M Papma, John C van Swieten
Magazine: Brain
Auteur: Lieke H.H. Meeter1,a, Tania F. Gendron2,a, Ana C. Sias3 , Lize C. Jiskoot1,4,5, Silvia P. Russo3 , Laura Donker Kaat1,6, Janne M. Papma1 , Jessica L. Panman1,5, Emma L. van der Ende1 , Elise G. Dopper1 , Sanne Franzen1 , Caroline Graff7,8, Adam L. Boxer3 , Howard J. Rosen3 , Raquel Sanchez-Valle9 , Daniela Galimberti10, Yolande A. L. Pijnenburg11, Luisa Benussi12, Roberta Ghidoni12, Barbara Borroni13, Robert Laforce Jr14, Marta del Campo15 , Charlotte E. Teunissen15 , Rick van Minkelen16, Julio
Magazine: Annals of Clinical and Translational Neurology
Auteur: Öijerstedt L, Andersson C, Jelic V, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R Jr, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonca A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Rohrer JD, Graff C; Genetic Frontotemporal Dementia Initiative (GENFI).
Magazine: Journal of Neurology, Neurosurgery and Psychiatry
Auteur: Author links open overlay panelJessica L.PanmanabLize C.JiskootabMark J.R.J.BoutsbcLieke H.H.MeeteraEmma L.van der EndeabJackie M.PoosabRogier A.FeisbcdAnneke J.A.KieviteRickvan MinkeleneElise G.P.DopperabfSerge A.R.B.RomboutsbcdJohn C.van SwietenagJanne M.Papmaa
Magazine: Neurobiology of Aging
Auteur: Katrina Moore , Rhian Convery , Martina Bocchetta , Mollie Neason , David M. Cash , Caroline Greaves , Lucy L. Russell , Mica T. M. Clarke , Georgia Peakman , John van Swieten , Lize Jiskoot , Fermin Moreno , Myriam Barandiaran , Raquel Sanchez-Valle , Barbara Borroni , Robert Laforce Jr , Marie-Claire Doré , Mario Masellis , Maria Carmela Tartaglia , Caroline Graff , Daniela Galimberti , James B. Rowe , Elizabeth Finger , Matthis Synofzik , Hans-Otto Karnath , Rik Vandenberghe , Alexandre de M
Magazine: Applied Neuropsychology: Adult
Auteur: Stephanie A. Chu1 , Taru M. Flagan1, Adam M. Staffaroni1, Lize C. Jiskoot2,3, Jersey Deng1, Salvatore Spina1, Liwen Zhang1, Virginia E. Sturm1, Jennifer S. Yokoyama1, William W. Seeley1, Janne M. Papma2, Dan H. Geschwind4, Howard J. Rosen1, Bradley F. Boeve5, Adam L. Boxer1, Hilary W. Heuer1, Leah K. Forsberg5, Danielle E. Brushaber5, Murray Grossman6, Giovanni Coppola4, Bradford C. Dickerson7, Yvette M. Bordelon4, Kelley Faber8, Howard H. Feldman9, Julie A. Fields5, Jamie C. Fong1, Tatiana Foro
Magazine: Annals of Clinical and Translational Neurology
Auteur: Author links open overlay panelKatrina MMooreBScaJenniferNicholasPhDcProfMurrayGrossmanPhDdCorey TMcMillanPhDdDavid JIrwinPhDdLaurenMassimoPhDdProfVivianna MVan DeerlinPhDdProfJason DWarrenPhDaProfNick CFoxMDaProfMartin NRossorMDaProfSimonMeadPhDbMartinaBocchettaPhDaProfBradley FBoeveMDeProfDavid SKnopmanMDeProfNeill RGraff-RadfordPhDfLeah KForsbergPhDeProfRosaRademakersPhDgProfZbigniew KWszolekMDfProfJohn Cvan SwietenPhDhLize CJiskootPhDhLieke HMeeterPhDhElise GPDopperPhDhJanne MPapmaPhDhProfJu
Magazine: The Lancet Neurology
Auteur: Peakman G, Russell LL, Convery RS, Nicholas JM, Van Swieten JC, Jiskoot LC, Moreno F, Sanchez-Valle R, Laforce R, Graff C, Masellis M, Tartaglia MC, Rowe JB, Borroni B, Finger E, Synofzik M, Galimberti D, Vandenberghe R, de Mendonça A, Butler CR, Gerhard A, Ducharme S, Le Ber I, Tagliavini F, Santana I, Pasquier F, Levin J, Danek A, Otto M, Sorbi S, Rohrer JD; Genetic FTD Initiative (GENFI).
Magazine: Journal of Neurology, Neurosurgery & Psychiatry
Auteur: Poos JM, Russell LL, Peakman G, Bocchetta M, Greaves CV, Jiskoot LC, van der Ende EL, Seelaar H, Papma JM, van den Berg E, Pijnenburg YAL, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia C, Finger E, Vandenberghe R, de Medonça A, Tagliavini F, Butler CR, Santana I, Ber IL, Gerhard A, Ducharme S, Levin J, Danek A, Otto M, Sorbi S, Pasquier F, van Swieten JC, Rohrer JD; Genetic FTD Initiative, GENFI.
Magazine: Alzheimer's & Dementia
Auteur: Manera AL, Dadar M, Van Swieten JC, Borroni B, Sanchez-Valle R, Moreno F, Laforce R Jr, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonca A, Tagliavini F, Santana I, Butler CR, Gerhard A, Danek A, Levin J, Otto M, Frisoni G, Ghidoni R, Sorbi S, Rohrer JD, Ducharme S, Collins DL; FTLDNI investigators; GENFI Consortium
Magazine: Journal of Neurology, Neurosurgery and Psychiatry
Auteur: Lize C. Jiskoot1,3 · Jackie M. Poos1,2 · Manon E. Vollebergh1 · Sanne Franzen1 · Judy van Hemmen1 · Janne M. Papma1 · John C. van Swieten1 · Roy P. C. Kessels4,5 · Esther van den Berg1
Magazine: Journal of Neurology
Auteur: Benussi A, Alberici A, Samra K, Russell LL, Greaves CV, Bocchetta M, Ducharme S, Finger E, Fumagalli G, Galimberti D, Jiskoot LC, Le Ber I, Masellis M, Nacmias B, Rowe JB, Sanchez-Valle R, Seelaar H, Synofzik M; GENFI Consortium, Rohrer JD,
Magazine: Alzheimer's & Dementia
Auteur: Wilke C, Reich S, van Swieten JC, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Bocchetta M, Todd E, Kuhle J, Barro C; Genetic Frontotemporal dementia Initiative (GENFI), Rohrer JD, Synofzik M.
Magazine: Annals of Neurology
Auteur: Lize C. Jiskoot, Jessica L. Panman, Lauren van Asseldonk, Sanne Franzen, Lieke H. H. Meeter, Laura Donker Kaat, Emma L. van der Ende, Elise G. P. Dopper, Reinier Timman, Rick van Minkelen, John C. van Swieten, Esther van den Berg & Janne M. Papma
Magazine: Journal of Neurology
Auteur: Bocchetta M, Todd EG, Peakman G, Cash DM, Convery RS, Russell LL, Thomas DL, Eugenio Iglesias J, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Galimberti D, Sanchez-Valle R, Laforce R, Moreno F, Synofzik M, Graff C, Masellis M, Carmela Tartaglia M, Rowe JB, Vandenberghe R, Finger E, Tagliavini F, de Mendonça A, Santana I, Butler CR, Ducharme S, Gerhard A, Danek A, Levin J, Otto M, Sorbi S, Le Ber I, Pasquier F, Rohrer JD; Genetic Frontotemporal dementia Initiative (GENFI).
Magazine: Neuroimage Clinical
Auteur: Premi E, Giunta M, Iraji A, Rachakonda S, Calhoun VD, Gazzina S, Benussi A, Gasparotti R, Archetti S, Bocchetta M, Cash D, Todd E, Peakman G, Convery R, van Swieten JC, Jiskoot L, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia C, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Butler CR, Santana I, Gerhard A, Le Ber I, Pasquier F, Ducharme S, Levin J, Danek A, Sorbi S, Otto M, Rohrer JD, Borroni B; Genetic Frontotemporal dementia I
Magazine: Neurobiology of Aging
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Samenvatting van de aanvraag
Frontotemporal dementia (FTD) is the second most common early onset dementia with various clinical, genetic and pathological subtypes. Genetic defects in three genes (MAPtau, progranulin and C9Orf72) account for 30 percent of the total FTD, with considerable variation in age of onset and disease course. These genetic defects are highly penetrant with a strong autosomal dominant inheritance pattern. Predicting disease onset in healthy mutation carriers is essential for determining the time window for future therapeutic interventions, in which subtype-specific biomarkers are extremely important to monitor their effect. The overall hypothesis is that conversion from pre - to symptomatic FTD and in its progression during the symptomatic stage can be quantitatively predicted and measured by changes in robust fluid and neuroimaging biomarkers. Our previous grant (2013) in Memorabel theme 1 was the first successful attempt to identify sensitive biomarkers of the earliest presymptomatic changes around conversion in a Dutch cohort of at-risk subjects. We (and others) observed early changes in presymptomatic individuals regarding grey matter volume, white matter integrity (by diffusion tensor imaging) and cerebral blood flow (by arterial spin labeling). Changes in neurofilament light chain protein (NfL) levels in both serum and cerebrospinal fluid appears to be sensitive fluid biomarker, predictive around conversion and prognostic during the disease process. Levels of poly(GP), as one of dipeptides, arise as a novel biomarker in mutation carriers of C9orf72 repeat expansions. Finally, we have identified profilin 1 (PFN1) levels as most promising biomarker by mass spectrometry of CSF in GRN patients versus presymptomatic carriers and controls. Longitudinal analyses over longer time periods in larger study populations are however scarce. Therefore, the current proposal will explicitly focus on longitudinal changes in neuroimaging and fluid biomarkers identified in the previous Memorabel project in order to define the predictive and prognostic value of these biomarkers, solely or in combination used at a single- subject level in the presymptomatic stage, around conversion, and during the disease stage. The current Dutch cohort of at-risk individuals for genetic FTD (n=160) constitutes families with GRN, MAPT and C9orf72 mutations and is built up since 2010. We will extend the longitudinal follow-up of this cohort, include new subjects and collaborate with our international partners in Europa and USA. This cohort has a structured protocol of a one or two-yearly assessment with the neurological examination, administration of rating scales and questionnaires, neuropsychological testing, structural, functional (ASL), DTI and resting state f-MRI, and blood collection and cerebrospinal fluid (in a subset). We also have the opportunity to carry out longitudinal analyses in the cohort of the European Genetic FTD Initiative (GENFI) cohort (currently >520 subjects), in which our center is the largest contributor. The much larger number of subjects in the GENFI cohort, and the cumulative number of converters during follow-up, enables us to detect more subtle differences. We will correlate neuroimaging results (VBM, DTI, ASL) and fluid proteins (NfL, poly(GP) and poly(GR), PFN1) to clinical parameters in a longitudinal analysis. This will provide us information about the pathophysiological and prognostic value of several potential biomarkers. Additionally, the longitudinal measurements will greatly facilitate the implementation of biomarkers in the clinical and trial setting for monitoring of disease activity and progression. Many participating at-risk subjects from families with genetic FTD experience increased stress and anxiety around research activities and important life decisions. Sixty percent of participants has given a positive response in our questionnnaire on mindfulness-based Stress Reduction (MBSR) training. We will implement training and psychological support in our research, and we will evaluate its beneficial effect in order to adapt it in the clinical setting. Our research plan fully addresses the challenge to understand the pre-clinical stage and earliest stage of FTD by longitudinal and multimodal biomarker analysis of the Dutch and GENFI cohort of presymptomatic and symptomatic carriers. These established cohorts provide the most ideal study subjects to elucidate the exact temporal sequence of and correlations between various biomarkers in both the conversion (pre – to symptomatic) period and during the disease. Correlative analyses between different biomarkers may identify determinants of clinical subtypes, and help to discriminate fast and slow progressors of genetic FTD, which is of importance in patient selection for therapeutical trials.