title: Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward.
abstract: Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule-associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer's, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model.
authors.affiliation: *ApconiX, BioHub at Alderley Park, Cheshire SK10 4TG, UK; ruth.roberts@apconix.com.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Roberts
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461;
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Eli Lilly & Co., Pharmacology/Toxicology Research Lilly Research Labs, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285;
authors.forename: David
authors.initials: D
authors.lastname: Calligaro
authors.affiliation: §Columbia University, New York, New York 10032;
authors.forename: Tomas R
authors.initials: TR
authors.lastname: Guilarte
authors.affiliation: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland 20993;
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.affiliation: US EPA, Toxicology Assessment Division, NHEERL, Research Triangle Park, North Carolona 27711;
authors.forename: David W
authors.initials: DW
authors.lastname: Herr
authors.affiliation: AbbVie, Inc., North Chicago, Illinois 60064;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudzik
authors.affiliation: Quanterix, Inc., Lexington, Massachusetts 02421;
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeromin
authors.affiliation: Covance, Inc., 8211 SciCor Drive, Indianapolis, Indiana 46214;
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kallman
authors.affiliation: **U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079;
authors.forename: Serguei
authors.initials: S
authors.lastname: Liachenko
authors.affiliation: Quanterix, Inc., Lexington, Massachusetts 02421;
authors.forename: James J
authors.initials: JJ
authors.lastname: Lynch
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: US EPA, Toxicology Assessment Division, NHEERL, Research Triangle Park, North Carolona 27711;
authors.forename: Virginia C
authors.initials: VC
authors.lastname: Moser
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.affiliation: **U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079;
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and.
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D004195:Disease Models, Animal; D005819:Genetic Markers; D006801:Humans; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D018570:Risk Assessment; D014116:Toxicology / Q000379:methods*; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D015415:Biomarkers; D005819:Genetic Markers
keywords: CSF; biomarker; imaging; neurotoxicity