From Acute Injury to Chronic Neurodegeneration: Molecular Mechanisms Linking Secondary Brain Injury to Long-Term Pathology

Abstract

Traumatic brain injury (TBI) initiates a complex cascade of pathophysiological events that have far-reaching consequences beyond the initial injury. This review examines the current state of the literature on the mechanisms underlying neurotrauma and neuroinflammation, with particular emphasis on the molecular cross-talk between these disparate pathways that ultimately precipitates the development of chronic traumatic encephalopathy (CTE). We integrate this mechanistic knowledge with potential diagnostic biomarkers, such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and advances in neuroimaging and machine learning-based predictive tools. Finally, we discuss the current therapeutic approaches under investigation, and highlight which molecular targets have yet to be explored for potential therapeutic development.

Keywords: Alzheimer’s Disease (AD); cellular and molecular mechanisms; chronic traumatic encephalopathy; cognitive decline; mitochondrial dysfunction; neurodegenerative disease; neuroinflammation; neurotrauma; oxidative stress; traumatic brain injury (TBI).

Figure 1

Comprehensive diagram of the neuroinflammatory cascade. Blue arrows indicate progression between stages of the cascade, while black arrows indicate relative changes in the quantity of a substance. Created in BioRender. Ahuja, C. (2025) https://BioRender.com/w7samd7.