Mild traumatic brain injury (mTBI) mostly causes transient symptoms, but repeated (r)mTBI can lead to neurodegenerative processes. Diagnostic tools to evaluate the presence of ongoing occult neuropathology are lacking. In a mouse model of rmTBI, we investigated MRI and plasma biomarkers of brain damage before chronic functional impairment arose. Anesthetized adult male and female C57BL/6J mice were subjected to rmTBI or a sham procedure. Sensorimotor deficits were evaluated up to 12 months post-injury in SNAP and Neuroscore tests. Cognitive function was assessed in the novel object recognition test at six and 12 months. Diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) were performed at six and 12 months to examine white matter and structural damage. Plasma levels of neurofilament light (NfL) were assessed longitudinally up to 12 months. Brain histopathology was performed at 12 months. Independent groups of mice were used to examine the effects of 2-, 7- and 14-days inter-injury intervals on acute plasma NfL levels and on hyperactivity. Twelve months after an acute transient impairment, sensorimotor functions declined again in rmTBI mice (p < 0.001 vs sham), but not earlier. Similarly, rmTBI mice showed memory impairment at 12 (p < 0.01 vs sham) but not at 6 months. White matter damage examined by DTI was evident in rmTBI mice at both six and 12 months (p < 0.001 vs sham). This was associated with callosal atrophy (p < 0.001 vs sham) evaluated by structural MRI. Plasma NfL at one week was elevated in rmTBI (p < 0.001 vs sham), and its level correlated with callosal atrophy at 12 months (Pearson r = 0.72, p < 0.01). Histopathology showed thinning of the corpus callosum and marked astrogliosis in rmTBI mice. The NfL levels were higher in mice subjected to short (2 days) compared with longer (7 and 14 days) inter-injury intervals (p < 0.05), and this correlated with hyperactivity in mice (Pearson r = 0.50; p < 0.05). These findings show that rmTBI causes white matter pathology detectable by MRI before chronic functional impairment. Early quantification of plasma NfL correlates with the degree of white matter atrophy one year after rmTBI and can serve to monitor the brain's susceptibility to a second mTBI, supporting its potential clinical application to guide the return to practice in sport-related TBI.

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