Cerebral amyloid β deposition and cognitive impairment after traumatic brain injury : Alzheimer’s disease secondary to TBI

Abstract

Background: Several pathological and epidemiologi­cal studies have demonstrated a possible relationship between traumatic brain injury (TBI) and Alzheimer’s disease (AD). However, how TBI contributes to the onset and progression of AD is unknown. We examined AD-related histopathological changes and cognitive impairment after TBI in the triple transgenic-AD model mice. We also examined amyloid β (Aβ) deposition in the brain using positron emission tomography (PET) in patients with chronic neuropsychological impairment after TBI.

Basic study: AD model mice and wild type (WT) mice were subjected to diffuse TBI using the weight-drop method or sham treatment. Spatial learning ability was evaluated using Morris water maze test in acute phase (4–7 days) and chronic phase (25–28 days) after TBI. Animals were sacrificed 7 or 28 days after TBI and expressions of amyloid precursor protein (APP) and Aβ in the hippocampus were examined using immunohistochemistry. In WT mice, TBI induced significant spatial learning deficit com­pared to sham-treated mice with increased Aβ deposition over the first 7 days, however, spatial learning ability was recovered to the control level with decreased Aβ deposition 4 weeks after TBI. In AD mice, compared to sham-treated mice, TBI mice demon­strated significant deficits in the spatial learning ability 4 weeks after TBI accompanied with increased Aβ depositions in the hippocampus.

Clinical study: Twelve patients (11 men and 1 woman, mean age 47.6 ± 6.2 years) were examined Aβ deposition in the brain using Pittsburgh Compound B (PIB) PET. PIB was positive in 1 patient (age 78), equivocal in 2 patients and negative in the other 9 patients. There were no relationships between the severity of injury, initial CT findings, elapsed time from the injury to examination, and the scores of neuropsychological tests and PIB deposition in the brain.

Conclusion: The profile of TBI-induced cognitive impairment and Aβ pathology was different between the WT and AD mice. TBI induces a significant increase in Aβ deposition in the hippocampus compared to control animals 28 days after TBI and this is associated with worse spatial learning ability only in AD mice. Moreover, the absence of Aβ deposition in most patients with chronic neuropsychological impairment after TBI does not support the premise that Aβ pathology progresses over time uni­formly in the traumatized brain. TBI-induced cognitive impair­ment concomitant by progres­sive Aβ pathology may be occurred only in aged brain with reduced cognitive reserve with silent Aβ burden.