Polypathology-associated neurodegeneration after remote head injury

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. TBI ranges from mild to severe and is a recognized risk factor for later neurodegenerative conditions including chronic traumatic encephalopathy (CTE), Alzheimer disease (AD) and Parkinson dis-ease (PD). The development of CTE is typically associated with repetitive exposure to mild TBI (mTBI), while a single moderate-to-severe TBI is considered a risk factor for AD and PD. Polypathology is common, and the lines between these conditions post TBI can be somewhat blurred. The mechanisms through which TBI leads to future neurodegeneration are not well understood. Het-erogeneity and distance from the injury or injuries and individual genetic and environ-mental factors make clinical studies difficult. We present the case of an 82-year-old man who died 4 years after developing a phenotypically mixed dementia with neuropsychiatric features and parkinsonism. He had a remote history of a severe TBI 40 years prior, following a road traffic accident which caused a large right frontal injury, requiring neurosurgical intervention. Post-mortem neuropathological examination demonstrated abnormal phosphorylated-Tau (p-Tau), beta-amyloid plaques (A beta) and alpha-synuclein deposition. Spatial immunohistochemical analysis demonstrated increased perivascu-lar accumulation of p-Tau with blood-brain barrier (BBB) disruption at the site of injury, which decreased with distance from the in-jury site. The appearances are suggestive of initial vascular disruption with persisting BBB disruption as a driver of the pathology.