Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study

被引：30

作者：

Wilke, Carlo ^{[1
,2
,3
]}

Reich, Selina ^{[1
,2
,3
]}

van Swieten, John C. ^{[4
]}

Borroni, Barbara ^{[5
]}

Sanchez-Valle, Raquel ^{[6
]}

Moreno, Fermin ^{[7
,8
]}

Laforce, Robert ^{[9
,10
]}

Graff, Caroline ^{[11
,12
]}

Galimberti, Daniela ^{[13
,14
]}

Rowe, James B. ^{[15
]}

Masellis, Mario ^{[16
]}

Tartaglia, Maria C. ^{[17
]}

Finger, Elizabeth ^{[18
]}

Vandenberghe, Rik ^{[19
,20
,21
]}

de Mendonca, Alexandre ^{[22
]}

Tagliavini, Fabrizio ^{[23
]}

Santana, Isabel ^{[24
,25
]}

Ducharme, Simon ^{[26
,27
]}

Butler, Chris R. ^{[28
,29
]}

Gerhard, Alexander ^{[30
,31
,32
]}

Levin, Johannes ^{[33
,34
,35
]}

Danek, Adrian ^{[33
]}

Otto, Markus ^{[36
,37
]}

Frisoni, Giovanni ^{[38
]}

Ghidoni, Roberta ^{[39
]}

Sorbi, Sandro ^{[40
,41
]}

Bocchetta, Martina ^{[42
]}

Todd, Emily ^{[42
]}

Kuhle, Jens ^{[43
,44
]}

Barro, Christian ^{[43
,44
,45
,46
]}

Rohrer, Jonathan D. ^{[42
]}

Synofzik, Matthis ^{[1
,2
,3
]}

机构：

[1] Univ Tubingen, Hertie Inst Clin Brain Res, Div Translat Genom Neurodegenerat Dis, Tubingen, Germany

[2] Univ Tubingen, Ctr Neurol, Tubingen, Germany

[3] Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[4] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[5] Univ Brescia, Ctr Neurodegenerat Disorders, Dept Clin & Expt Sci, Brescia, Italy

[6] Univ Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Neurol Serv, Hosp Clin,Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain

[7] Donostia Univ Hosp, Dept Neurol, Cognit Disorders Unit, San Sebastian, Spain

[8] Biodonostia Hlth Res Inst, Neurosci Area, San Sebastian, Spain

[9] Univ Laval, Clin Interdisciplinaire Memoire, Dept Sci Neurol, CHU Quebec, Quebec City, PQ, Canada

[10] Univ Laval, Fac Med, Quebec City, PQ, Canada

[11] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr,Bioclinicum, Solna, Sweden

[12] Karolinska Univ Hosp, Unit Hereditary Dementias, Theme Aging, Solna, Sweden

[13] Fdn IRCCS Osped Policlin, Milan, Italy

[14] Univ Milan, Ctr Dino Ferrari, Milan, Italy

[15] Univ Cambridge, Dept Clin Neurosci, Cambridge, England

[16] Univ Toronto, Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Toronto, ON, Canada

[17] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada

[18] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada

[19] Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium

[20] Univ Hosp Leuven, Neurol Serv, Leuven, Belgium

[21] Katholieke Univ Leuven, Leuven Brain Inst, Leuven, Belgium

[22] Univ Lisbon, Fac Med, Lisbon, Portugal

[23] Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy

[24] Univ Coimbra, Univ Hosp Coimbra HUC, Fac Med, Neurol Serv, Coimbra, Portugal

[25] Univ Coimbra, Fac Med, Ctr Neurosci & Cell Biol, Coimbra, Portugal

[26] McGill Univ, McGill Univ Hlth Ctr, Dept Psychiat, Montreal, PQ, Canada

[27] McGill Univ, McConnell Brain Imaging Ctr, Montreal Neurol Inst, Montreal, PQ, Canada

[28] Univ Oxford, Nuffield Dept Clin Neurosci, Med Sci Div, Oxford, England

[29] Imperial Coll London, Dept Brain Sci, London, England

[30] Univ Manchester, Fac Med Biol & Hlth, Div Neurosci & Expt Psychol, Manchester, Lancs, England

[31] Essen Univ Hosp, Dept Geriatr Med, Essen, Germany

[32] Essen Univ Hosp, Dept Nucl Med, Essen, Germany

[33] Ludwig Maximilians Univ Munchen, Neurol Klin, Munich, Germany

[34] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[35] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[36] Univ Ulm, Dept Neurol, Ulm, Germany

[37] Martin Luther Univ Halle Wittenberg, Dept Neurol, Halle, Saale, Germany

[38] Inst Ricovero & Cura Carattere Sci, Ist Ctr San Giovanni di Dio Fatebenefratelli, Brescia, Italy

[39] IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Mol Markers Lab, Brescia, Italy

[40] Univ Florence, Dept Neurofarba, Florence, Italy

[41] IRCCS Fdn Don Carlo Gnocchi, Florence, Italy

[42] UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, London, England

[43] Univ Basel, Univ Hosp Basel, MS Ctr, Neurol Clin & Policlin, Basel, Switzerland

[44] Univ Basel, Univ Hosp Basel, Res Ctr Clin Neuroimmunol & Neurosci Basel RC2NB, Basel, Switzerland

[45] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA

[46] Harvard Med Sch, Boston, MA 02115 USA

来源：

ANNALS OF NEUROLOGY | 2022年 / 91卷 / 01期

基金：

欧盟地平线“2020”; 瑞士国家科学基金会; 英国医学研究理事会;

关键词：

NEUROFILAMENT LIGHT-CHAIN; HEXANUCLEOTIDE REPEAT; DISEASE PROGRESSION; MUTATIONS; CRITERIA; C9ORF72; TAU; FTD;

D O I：

10.1002/ana.26265

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. Methods We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. Results In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Interpretation Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2021

引用

页码：33 / 47

页数：15

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