Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer's Disease

被引:302
作者
Fagan, Anne M. [1 ,2 ]
Xiong, Chengjie [2 ,3 ]
Jasielec, Mateusz S. [2 ,3 ]
Bateman, Randall J. [1 ,2 ]
Goate, Alison M. [1 ,2 ,4 ]
Benzinger, Tammie L. S. [2 ,5 ]
Ghetti, Bernardino [6 ]
Martins, Ralph N. [7 ]
Masters, Colin L. [8 ]
Mayeux, Richard [9 ,10 ]
Ringman, John M. [11 ]
Rossor, Martin N. [12 ]
Salloway, Stephen [13 ,14 ]
Schofield, Peter R. [15 ,16 ]
Sperling, Reisa A. [17 ]
Marcus, Daniel [2 ,5 ]
Cairns, Nigel J. [1 ,2 ,18 ]
Buckles, Virginia D. [1 ,2 ]
Ladenson, Jack H. [18 ]
Morris, John C. [1 ,2 ,18 ]
Holtzman, David M. [1 ,2 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
[5] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA
[6] Indiana Univ, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA
[7] Edith Cowan Univ, WA Ctr Alzheimers Res & Care, Perth, WA 6009, Australia
[8] Univ Melbourne, Mental Hlth Res Inst, Melbourne, Vic 3052, Australia
[9] Columbia Univ, Taub Inst, Dept Neurol, New York, NY 10032 USA
[10] Columbia Univ, Sergievsky Ctr, New York, NY 10032 USA
[11] Univ Calif Los Angeles, Mary S Easton Ctr Alzheimers Dis Res, Dept Neurol, Los Angeles, CA 90095 USA
[12] UCL, Dementia Res Ctr, London WC1N 3BG, England
[13] Brown Univ, Butler Hosp, Warren Alpert Med Sch, Dept Neurol, Providence, RI 02906 USA
[14] Brown Univ, Butler Hosp, Warren Alpert Med Sch, Dept Psychiat, Providence, RI 02906 USA
[15] Neurosci Res Australia, Sydney, NSW 2031, Australia
[16] Univ New S Wales, Sch Med Sci, Sydney, NSW 2031, Australia
[17] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Brigham & Womens Hosp, Boston, MA 02129 USA
[18] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
关键词
CEREBROSPINAL-FLUID TAU; AMYLOID-BETA-PROTEIN; MILD COGNITIVE IMPAIRMENT; A-BETA; IN-VIVO; NATIONAL INSTITUTE; PHOSPHORYLATED TAU; ENTORHINAL CORTEX; DEMENTIA; PRESENILIN-1;
D O I
10.1126/scitranslmed.3007901
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Clinicopathological evidence suggests that the pathology of Alzheimer's disease ( AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-beta(1-42) (A beta(1-42)) associated with the presence of Ab plaques, and elevated concentrations of CSF tau, ptau(181) (phosphorylated tau(181)), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
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页数:16
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