A neurovascular perspective for long-term changes after brain trauma

Abstract

Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on changes in the neurovascular unit (NVU), including neuronal interactions with glia and blood vessels at the blood-brain barrier (BBB). Post-traumatic changes in cerebral blood-flow, BBB structures and function, as well as mechanistic pathways associated with brain aging and neurodegeneration are presented from clinical and experimental reports. Based on the literature, increased attention on BBB changes should be integrated in studies characterizing TBI outcome and may provide a meaningful therapeutic target to resolve detrimental post-traumatic dysfunction.

Figure 1. Summary timeline of pathophysiological cascades following TBI

Existing clinical and experimental literature agree on a fairly consistent description of the course of events within days and weeks following TBI (solid lines) compared to expected control levels over time (dashed line in center). The primary injury is depicted as the moment of impact at Time 0, which can result in tissue damage and necrosis to the NVU, often with the local destruction of the blood vessels and presence of bleeding. However, further clinical studies with experimental verifications are necessary to address the nature and time-line of several secondary injury cascades and related long-term modifications post-TBI which are currently unknown (dotted lines). The schematic conveys a generalized post-injury timeline where behavior (gold line) is used to denote a wide range of motor and neurobehavioral dysfunctions. Thus, behavioral impairment occurs within minutes of most TBI injuries and partial recovery may occur in the weeks and months following injury, depending on the specific behavior, with data indicating continued neurobehavioral impairment years later, and little data available for post-TBI assessment during advanced age. Some possible underlying mechanisms accounting for the acute phase of behavioral impairment in the first week post-TBI may be: decreased cerebral blood flow and hypometabolism (purple line), increased edema and brain swelling (brown line), increased BBB permeability measured with staining of IgG extravasation (green line), increased inflammation, excitotoxicity, and oxidative stress (blue line), and increased neuropathological accumulation of proteins associated with neurological disease (pink line). Notably, some post-TBI changes are transient and return close to control levels, such as edema and brain swelling (brown line) and BBB permeability (green line). On the other hand, long-lasting behavioral dysfunction might be explained by one or all of the remaining pathophysiological cascades that are not short-lived, but stabilize at a new substandard level. Thus, there is a need and an opportunity to explore these cascades for the development of new drugs targeting long-term dysfunctions after TBI. (TBI: traumatic brain injury; NVU: neurovascular unit; BBB: blood-brain barrier; IgG: immunoglobulin G; Aβ: beta-amyloid; α-syn: alpha synuclein)

Figure 2. Timecourse of IgG extravasation following juvenile TBI

Coronal sections of rats given a controlled cortical impact (CCI) at a juvenile age, post-natal day 17 (P17), are evaluated after 1, 3, 7, 60, and 180 days post-injury. The CCI was given to the right somatosensory cortex overlying the hippocampus (top right of each coronal section). IgG extravasation levels are elevated (bright green staining) near the injury site and surrounding tissue at 1 and 3 days, much lower at 7 days, with the exception of high levels retained close to the impact site. At 60 and 180 days after juvenile impact, IgG is not detected near the injury site and staining is observed in regions without a barrier, such as the median eminence.

Figure 3. Proposed model of physiological function during normal conditions and after TBI

Several reports indicate that cognitive patterns may follow cerebrovascular physiological function, and this model gives a view of general temporal relationships expected in normal conditions (black solid and dashed lines) and following traumatic brain injury (TBI, red solid and dashed lines). The reports from the literature suggest that functions of the blood-brain barrier (BBB) and behavioral/cognitive processes are interconnected, and steadily improving during early developmental stages (black solid and dashed lines). They reach a maximal point that remains a steady plateau during adult years, yet eventually succumbs to normal processes of aging that cause a decline in late adulthood, and which continues to drop with advancing age. A TBI injury early in life at a critical developmental period causes a permanent disruption in these normal patterns. Immediately after injury, there is a temporary sharp drop in structural and physiological functions of the BBB concomitant with behavioral/cognitive processes (red solid and dashed lines). With time, recovery occurs, but in many cases it can only approach but never quite reach normal levels. Possibly, a new baseline of stable BBB and cognitive function are reached during adulthood, but this period is short-lived due to accumulating processes of aging. Thus, TBI injury has detrimental effects in the short-term which are partially restored but never fully recover over an individual’s lifetime, and which may contribute to enhanced vulnerability to neurodegenerative processes, ongoing cerebrovascular dysfunction, and behavioral as well as cognitive deteriorations.