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Neurobiomarkers: Basic Aspects and Their Relevance in Nonclinical Studies.
Andrea Greiter-Wilke1, Nicolau Beckmann2, Warren E Glaab3
1F. Hoffmann-La Roche, Basel, Switzerland.
Toxicologic Pathology
|May 6, 2025
Summary
This study highlights neural biomarkers and functional tests in drug development to detect nervous system injury. Integrating these with imaging and pathology improves neurotoxicity prediction.
Area of Science:
- Toxicologic Pathology
- Neuroscience
- Drug Development
Background:
- Nonclinical studies are crucial for detecting drug-induced nervous system alterations.
- Neural biomarkers and functional endpoints aid in identifying peripheral (PNS) and central nervous system (CNS) injuries.
- Pathologists play a key role in correlating biomarkers with microscopic findings for clinical translation.
Purpose of the Study:
- To review the significance of neural biomarkers and functional endpoints in nonclinical neurotoxicity assessments.
- To emphasize the clinical translation potential of these predictive tools.
- To discuss the integration of various methods for enhanced neurotoxicity prediction.
Main Methods:
- Evaluation of fluid-based biomarkers: Neurofilament Light Chain (NF-L), Nonspecific Enolase (NSE), Tubulin Associated Unit (TAU), and Glial Fibrillar Associated Protein (GFAP) in blood/cerebrospinal fluid (CSF).
- Inclusion of 15 in-vivo studies using CNS and PNS toxicants.
- Application of safety pharmacology evaluations (e.g., Irwin screen/functional observation battery - FOB) and follow-up tests (e.g., nerve conduction velocity).
- Utilization of noninvasive imaging modalities: MRI, nuclear imaging, CT, and ultrasound.
Main Results:
- Discussed key neural biomarkers (NF-L, NSE, TAU, GFAP) for detecting CNS and PNS alterations.
- Presented safety pharmacology data on behavioral and functional changes in rodents and nonrodents.
- Highlighted the utility of advanced imaging techniques in preclinical neurotoxicity studies.
- Demonstrated the value of integrating diverse methodologies for comprehensive assessment.
Conclusions:
- Integrating neural biomarkers, safety pharmacology, advanced imaging, and histopathology significantly enhances the prediction of drug-induced neurotoxicity.
- These approaches are vital for ensuring drug safety during development.
- The findings support the critical role of toxicologic pathologists in interpreting complex neurotoxicity data.
