Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Abstract

Traumatic brain injury (TBI) is a risk factor for dementia, with studies describing a mixed neurodegenerative pathology in late survivors. However, the mechanisms driving this post-TBI neurodegeneration remain elusive. Increasingly, blood brain barrier (BBB) disruption is recognized in a range of neurological disorders, including dementias; although little is known of the consequences of TBI on the BBB. From the Glasgow TBI Archive autopsy cases of single, moderate or severe TBI (n=70) were selected to include a range of survivals from acute (10h to 13days) to long-term (1 to 47years) survival, together with age-matched, uninjured controls (n=21). Multiple brain regions were examined for fibrinogen (FBG) and immunoglobulin G (IgG) immunohistochemistry. Following TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multi-focal, abnormal, perivascular and parenchymal FBG and IgG immunostaining localized to grey matter, with preferential distribution towards the crests of gyri and deep neocortical layers. In contrast, where present, controls showed only limited, localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.

Traumatic brain injury results in acute rarefication of the vascular network

“…In human studies, cerebral blood flow (CBF) was reduced early and continued to exhibit hypoperfusion 14d after TBI 11 . Other vascular findings in TBI patients include loss of autoregulatory capacity 22 , decreased cerebrovascular reactivity 23,24 , and persistent blood brain barrier leakage 25 . Further, in severe human TBI direct observation of the peri-contusional vasculature reported decreased vessel density but no apparent alteration in flow 13 .…”

“…One can readily speculate that cerebral autoregulation, blood flow and other factors including modifications to elements of the neurovascular unit are altered, perhaps permanently. Clinically, early vascular alterations are thought to lead to long term changes in the blood brain barrier 25 . Finally, vascular reductions and subsequent repair may underlie some of the abnormal connectivity that has been reported using blood oxygen level dependent (BOLD) resting state functional MRI after TBI 33 .…”

Environmental enrichment attenuates the blood brain barrier dysfunction induced by the neonatal hypoxia‐ischemia

“…The importance of the BBB has been well-documented in physiological and pathological conditions such as brain ischemia, dementia and Parkinson's disease (Abbott, 2013;Cardoso et al, 2010;Hay et al, 2015;Krueger et al, 2015;Lee and Pienaar, 2014). Such dysfunction has a strong relationship with damage to the neuropil and disturbed brain function (Wolburg and Lippoldt, 2002).…”

High levels of plasma fibrinogen are related to post‐stroke cognitive impairment

“…In another study, fibrinogen mediated regulation of the TGF-beta receptor pathway in astrocytes. Additionally, traumatic injuries can lead to destruction of the BBB and then lead to cognitive dysfunction (Hay, Johnson, Young, Smith, & Stewart, 2015 As a result, we hypothesize that elevated levels of plasma fibrinogen may damage cognitive function through the above mechanisms. In addition, in brain pathology, including ischemic stroke and AD, disruption of the BBB allows blood proteins to enter the brain, followed by edema and neuronal damage.…”