Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

被引：47

作者：

Meeter, Lieke H. H. ^{[1
,2
]}

Gendron, Tania F. ^{[3
]}

Sias, Ana C. ^{[4
]}

Jiskoot, Lize C. ^{[1
,2
,5
,6
]}

Russo, Silvia P. ^{[4
]}

Kaat, Laura Donker ^{[1
,2
,7
]}

Papma, Janne M. ^{[1
,2
]}

Panman, Jessica L. ^{[1
,2
,6
]}

van der Ende, Emma L. ^{[1
,2
]}

Dopper, Elise G. ^{[1
,2
]}

Franzen, Sanne ^{[1
,2
]}

Graff, Caroline ^{[8
,9
]}

Boxer, Adam L. ^{[4
]}

Rosen, Howard J. ^{[4
]}

Sanchez-Valle, Raquel ^{[10
]}

Galimberti, Daniela ^{[11
]}

Pijnenburg, Yolande A. L. ^{[12
,13
]}

Benussi, Luisa ^{[14
]}

Ghidoni, Roberta ^{[14
]}

Borroni, Barbara ^{[15
]}

Laforce, Robert, Jr. ^{[16
]}

del Campo, Marta ^{[17
]}

Teunissen, Charlotte E. ^{[17
]}

van Minkelen, Rick ^{[18
]}

Rojas, Julio C. ^{[4
]}

Coppola, Giovanni ^{[19
,20
]}

Geschwind, Dan H. ^{[19
,20
]}

Rademakers, Rosa ^{[3
]}

Karydas, Anna M. ^{[4
]}

Oijerstedt, Linn ^{[8
,9
]}

Scarpini, Elio ^{[11
]}

Binetti, Giuliano ^{[14
,21
]}

Padovani, Alessandro ^{[15
]}

Cash, David M. ^{[5
,22
]}

Dick, Katrina M. ^{[5
]}

Bocchetta, Martina ^{[5
]}

Miller, Bruce L. ^{[4
]}

Rohrer, Jonathan D. ^{[5
]}

Petrucelli, Leonard ^{[3
]}

van Swieten, John C. ^{[1
,2
,23
]}

Lee, Suzee E. ^{[4
]}

机构：

[1] Erasmus MC, Alzheimer Ctr Rotterdam, POB 2040, NL-3000 CA Rotterdam, Netherlands

[2] Erasmus MC, Dept Neurol, POB 2040, NL-3000 CA Rotterdam, Netherlands

[3] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[4] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, 675 Nelson Rising Lane,MC 1207, San Francisco, CA 94158 USA

[5] UCL, Dept Neurodegenerat Dis, Dementia Res Ctr, Inst Neurol, London WC1N 3BG, England

[6] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands

[7] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands

[8] Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept NVS, S-14157 Huddinge, Sweden

[9] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Geriatr Med, S-14186 Stockholm, Sweden

[10] Inst Invest Biomed August Pi & Sunyer, Hosp Clin, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Villarroel 170, Barcelona 17008036, Spain

[11] Univ Milan, Fdn Ca Granda, IRCSS Osped Policlin, Milan, Italy

[12] Vrije Univ Amsterdam Med Ctr, Amsterdam Neurosci, Alzheimer Ctr, POB 7057, NL-1007 MB Amsterdam, Netherlands

[13] Vrije Univ Amsterdam Med Ctr, Amsterdam Neurosci, Dept Neurol, POB 7057, NL-1007 MB Amsterdam, Netherlands

[14] IRCCS Ctr San Giovanni di Dio Fatebenefratelli, Mol Markers Lab, Via Pilastroni 4, I-25125 Brescia, Italy

[15] Univ Brescia, Neurol Unit, Dept Clin & Expt Sci, Ctr Neurodegenerat Dis, Brescia, Italy

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

[17] Vrije Univ Amsterdam Med Ctr, Amsterdam Neurosci, Dept Clin Chem, Neurochem Lab, POB 7057, NL-1007 MB Amsterdam, Netherlands

[18] Erasmus MC, Dept Clin Genet, POB 2040, NL-3000 CA Rotterdam, Netherlands

[19] Univ Calif Los Angeles, Dept Neurol, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza, Los Angeles, CA 90024 USA

[20] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat, 760 Westwood Plaza, Los Angeles, CA 90024 USA

[21] IRCCS Ctr San Giovanni Dio Fatebenefratelli, MAC Memory Ctr, Via Pilastroni 4, I-25125 Brescia, Italy

[22] UCL, Translat Imaging Grp, Ctr Med Image Comp, London NW1 2HE, England

[23] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, POB 7057, NL-1007 MB Amsterdam, Netherlands

来源：

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY | 2018年 / 5卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会; 荷兰研究理事会;

关键词：

HEXANUCLEOTIDE REPEAT EXPANSION; FRONTOTEMPORAL DEMENTIA; LIGHT-CHAIN; BEHAVIORAL VARIANT; BIOMARKER; DEGENERATION; PROGRANULIN; TOXICITY; MARKER; BLOOD;

D O I：

10.1002/acn3.559

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

引用

页码：583 / 597

页数：15

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