The Blood Brain Barrier Injury in CTE

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The Blood Brain Barrier Injury in CTE

The blood brain barrier (BBB) is a vital protective structure formed by cells lining the brain capillaries that are tightly joined to one another that prevent most substances from entering the brain.  A recent study of athletes retired from combat or collision sports revealed that a leaky BBB is the primary mechanism by which repeated head injuries (RHI) lead to long term cognitive decline and eventually Chronic Traumatic Encephalopathy (CTE).

Traumatic encephalopathy syndrome (TES) is associated with a history of RHI and describes the clinical symptoms exhibited by a living person suspected of having CTE based on cognitive, behavioral, and other related features, a progressive course of disease; and clinical features not fully accounted for by another condition.  CTE is also linked to RHI but can only definitively be diagnosed by autopsy from the presence of fibrils containing tau protein highly modified by added phosphate groups (p-tau).  Phosphate groups consist of a central phosphorus atom bonded to four oxygen atoms. There is also aggregation of astrocytes, star-shaped glial cells in the brain and spinal cord that play crucial roles in supporting neurons They lie at the depths of the sulci, the shallow depressions in the cerebral cortex. Think of the folds you see on the surface in pictures of the brain.  Before death, early CTE symptoms often involve behavioral and mental health changes, such as depression, anxiety, impulsivity, and aggression. Later stages may include cognitive decline, memory loss, impaired judgment, executive dysfunction, and dementia-like symptoms. Physical symptoms can include tremors, balance problems, and motor neuron disease-like features. All these features contribute to a CTE diagnosis.

BBB disruption has been observed in CTE cases confirmed by autopsy.  Scientists in this recent study theorized that BBB disruption could be used to detect TES years after repetitive head injuries.  They used Dynamic Contrast Enhanced magnetic resonance imaging (DCE-MRI) of 47 retired athletes to show that BBB disruption was present years after retirement. DCE-MRI uses a gadolinium-based contrast agent which is small enough to pass through spaces between cells except where the BBB is intact.  If the BBB is disrupted, the contract agent can be seen leaking into the brain tissue in living individuals. They examined retired contact sport athletes a minimum of 1 year out of sports like rugby, boxing, football, etc. and non-contact sport controls such as rowing.  They compared MRI scans of living rugby players and boxers with post-mortem tissue from athletes diagnosed with CTE.  

The BBB acts as a protective layer allowing entry of essential nutrients into the brain while keeping toxins and inflammatory proteins and cells out. These results strongly associate contact/collision sports with an increased risk of BBB pathology and subsequent cognitive decline years after retiring. The leaky BBB in athletes with CTE allowed inflammatory proteins and cells to enter their brains. They trigger a cascade of events that lead to damage including the build up of p-tau, a known CTE marker, as well as markers of neuronal loss.  The retired athletes with the most extensive BBB leakage also scored significantly lower on cognitive tests measuring memory and executive function.

These results suggest that DCE-MRI of the BBB could serve as an early diagnostic marker for athletes at highest risk of developing future brain diseases, potentially while they are still playing or soon after retirement.  Earlier studies had reported that active American football players revealed pathological BBB changes in ~40% of athletes. They have also shown BBB disruption in active rugby players and mixed martial arts fighters in the days and months after exposure to RHI. Early interventions with existing or new drugs could slow or prevent brain disease progression. It will be important to expand these studies to athletes at various career stages to determine when BBB leakage actually begins.  It will also be important to look at many more types of sports to understand which activities can cause BBB leakage.