Suzanne E Schindler1, Yan Li2, Kaitlin W Todd2, Elizabeth M Herries3, Rachel L Henson4, Julia D Gray4, Guoqiao Wang2, Danielle L Graham5, Leslie M Shaw6, John Q Trojanowski7, Jason J Hassenstab1, Tammie L S Benzinger8, Carlos Cruchaga9, Mathias Jucker10, Johannes Levin11, Jasmeer P Chhatwal12, James M Noble13, John M Ringman14, Neill R Graff-Radford15, David M Holtzman4, Jack H Ladenson3, John C Morris1, Randall J Bateman4, Chengjie Xiong16, Anne M Fagan17. 1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. 2. Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. 3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. 4. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. 5. Biomarkers, Research and Early Development, Biogen, Cambridge, MA, USA. 6. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. 9. Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. 10. German Center for Neurodegenerative Diseases (DZNE), Germany; Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 11. German Center for Neurodegenerative Diseases (DZNE), Germany; Department of Neurology, Ludwig Maximilians University, Munich, Germany. 12. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 13. Department of Neurology, Columbia University Medical Center, New York City, NY, USA. 14. Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. 15. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. 16. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. 17. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: fagana@wustl.edu.
Abstract
INTRODUCTION: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
INTRODUCTION: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS:CSFneurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSFSNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
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