Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

被引：639

作者：

Preische, Oliver ^{[1
,2
,3
]}

Schultz, Stephanie A. ^{[4
,5
]}

Apel, Anja ^{[1
,2
,3
]}

Kuhle, Jens ^{[6
,7
]}

Kaeser, Stephan A. ^{[1
,2
,3
]}

Barro, Christian ^{[6
,7
]}

Graeber, Susanne ^{[1
]}

Kuder-Buletta, Elke ^{[1
,42
]}

LaFougere, Christian ^{[1
]}

Laske, Christoph ^{[1
,2
,3
,42
]}

Voeglein, Jonathan ^{[8
,9
]}

Levin, Johannes ^{[8
,9
,40
]}

Masters, Colin L. ^{[10
]}

Martins, Ralph ^{[11
,12
,36
]}

Schofield, Peter R. ^{[13
,14
]}

Rossor, Martin N. ^{[15
]}

Graff-Radford, Neill R. ^{[16
]}

Salloway, Stephen ^{[17
,27
]}

Ghetti, Bernardino ^{[18
,19
,29
]}

Ringman, John M. ^{[20
]}

Noble, James M. ^{[21
]}

Chhatwal, Jasmeer ^{[22
,31
]}

Goate, Alison M. ^{[23
]}

Benzinger, Tammie L. S. ^{[4
,5
]}

Morris, John C. ^{[4
,5
]}

Bateman, Randall J. ^{[4
,5
]}

Wang, Guoqiao ^{[4
,5
]}

Fagan, Anne M. ^{[4
,5
]}

McDade, Eric M. ^{[4
,5
]}

Gordon, Brian A. ^{[4
,5
]}

Jucker, Mathias ^{[1
,2
,3
,42
]}

Allegri, Ricardo ^{[24
]}

Amtashar, Fatima ^{[25
]}

Bateman, Randall ^{[25
]}

Benzinger, Tammie ^{[25
]}

Berman, Sarah ^{[26
]}

Bodge, Courtney ^{[27
]}

Brandon, Susan ^{[25
]}

Brooks, William ^{[28
]}

Buck, Jill ^{[29
]}

Buckles, Virginia ^{[25
]}

Chea, Sochenda ^{[30
]}

Chhatwal, Jasmeer ^{[22
,31
]}

Chrem, Patricio ^{[24
]}

Chui, Helena ^{[32
]}

Cinco, Jake ^{[33
]}

Clifford, Jack ^{[30
]}

Cruchaga, Carlos ^{[25
]}

D'Mello, Mirelle ^{[28
]}

Donahue, Tamara ^{[25
]}

机构：

[1] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[2] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, Tubingen, Germany

[3] Univ Tubingen, Dept Psychiat & Psychotherapy, Tubingen, Germany

[4] Washington Univ, Sch Med, Dept Radiol, Dept Neurol, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA

[6] Univ Basel, Neurol Clin & Policlin, Dept Med, Univ Hosp Basel, Basel, Switzerland

[7] Univ Basel, Neurol Clin & Policlin, Dept Biomed & Clin Res, Univ Hosp Basel, Basel, Switzerland

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

[9] Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany

[10] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Neurodegenerat Div, Parkville, Vic, Australia

[11] Edith Cowan Univ, Sch Med Hlth & Sci, Joondalup, WA, Australia

[12] Macquarie Univ, Dept Biomed Sci, Sydney, NSW, Australia

[13] Neurosci Res Australia, Randwick, NSW, Australia

[14] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[15] UCL, Queen Sq Inst Neurol, Dept Neurodegenerat, Dementia Res Ctr, London, England

[16] Mayo Clin Jacksonville, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA

[17] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA

[18] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA

[19] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

[20] USC, Keck Sch Med, Dept Neurol, Los Angeles, CA USA

[21] Columbia Univ, Med Ctr, Dept Neurol, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[22] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA

[23] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[24] Inst Neurol Res, FLENI, Fdn Lucha Enfermedades Neurolog Infancia, Buenos Aires, DF, Argentina

[25] Washington Univ, Sch Med, St Louis, MO USA

[26] Univ Pittsburgh, Pittsburgh, PA USA

[27] Brown Univ, Butler Hosp, Providence, RI 02912 USA

[28] Neurosci Res Australia, Sydney, NSW, Australia

[29] Indiana Univ, Bloomington, IN USA

[30] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA

[31] Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA

[32] Univ Southern Calif, Los Angeles, CA USA

[33] UCL, London, England

[34] Univ Calif San Diego, San Diego, CA 92103 USA

[35] Osaka City Univ, Osaka, Japan

[36] Edith Cowan Univ, Perth, WA, Australia

[37] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[38] Columbia Univ, New York, NY USA

[39] Hirosaki Univ, Aomori, Japan

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

[41] Niigata Univ, Niigata, Japan

[42] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[43] Univ Michigan, Ann Arbor, MI 48109 USA

[44] Asan Med Ctr, Seoul, South Korea

[45] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA

[46] Univ Melbourne, Melbourne, Vic, Australia

[47] Univ Tokyo, Tokyo, Japan

[48] Univ Calif San Francisco, San Francisco, CA 94143 USA

来源：

NATURE MEDICINE | 2019年 / 25卷 / 02期

基金：

美国国家科学基金会; 美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

AUTOSOMAL-DOMINANT; LIGHT-CHAIN; NEURONAL DAMAGE; BIOMARKER; PROTEIN; BLOOD; INDIVIDUALS; MARKER; ONSET; CSF;

D O I：

10.1038/s41591-018-0304-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-beta deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.

引用

页码：277 / +

页数：17

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