Brain injury-induced dysfunction of the blood brain barrier as a risk for dementia

The blood-brain barrier (BBB) is a complex and dynamic physiological interface between brain parenchyma and cerebral vasculature. It is composed of closely interacting cells and signaling molecules that regulate movement of solutes, ions, nutrients, macromolecules, and immune cells into the brain and removal of products of normal and abnormal brain cell metabolism. Dysfunction of multiple components of the BBB occurs in aging, inflammatory diseases, traumatic brain injury (TBI, severe or mild repetitive), and in chronic degenerative dementing disorders for which aging, inflammation, and TBI are considered risk factors. BBB permeability changes after TBI result in leakage of serum proteins, influx of immune cells, perivascular inflammation, as well as impairment of efflux transporter systems and accumulation of aggregation-prone molecules involved in hallmark pathologies of neurodegenerative diseases with dementia. In addition, cerebral vascular dysfunction with persistent alterations in cerebral blood flow and neurovascular coupling contribute to brain ischemia, neuronal degeneration, and synaptic dysfunction. While the idea of TBI as a risk factor for dementia is supported by many shared pathological features, it remains a hypothesis that needs further testing in experimental models and in human studies. The current review focusses on pathological mechanisms shared between TBI and neurodegenerative disorders characterized by accumulation of pathological protein aggregates, such as Alzheimer's disease and chronic traumatic encephalopathy. We discuss critical knowledge gaps in the field that need to be explored to clarify the relationship between TBI and risk for dementia and emphasize the need for longitudinal in vivo studies using imaging and biomarkers of BBB dysfunction in people with single or multiple TBI.