A silent epidemic

C&I Issue 10, 2013

A violent strike to the head, which causes the brain to bump against the inside of the skull, or when an object, such as a bullet, penetrates the brain, can lead to severe traumatic brain injury (TBI). Such injuries can cause bleeding or swelling of the brain, as well as damage to the nerve cells. In some cases, a severe TBI can lead to coma or death. The US Centre for Disease Control and Prevention, estimates that each year in the US alone, around 1.7m people sustain a severe TBI, resulting in 52,000 deaths.

A mild TBI (mTBI) or concussion can cause dizziness and headaches, and affect mood and behaviour. These symptoms usually go away after a few days or weeks. A moderate TBI may cause lasting problems with thinking and concentrating, and can also affect short-term memory.

Furthermore, some patients, who have been subjected to repetitive head injury, can go on to develop symptoms similar to neurodegenerative diseases such as Alzheimer’s disease (AD). This collection of symptoms – including changes in memory, mood, personality, behaviour and movement – is referred to as chronic traumatic encephalopathy (CTE).

Doctors use clinical examination and neuroimaging to recognise the extremes of the spectrum of TBI, but it’s difficult to assess whether the brain has been injured. Emerging evidence suggests that mTBI is not necessarily ‘mild’ because about 15% of individuals with mTBI develop persistent problems, says Douglas Smith of the Center for Brain Injury and Repair at the University of Pennsylvania, US. Even in mild cases, there is damage to the brain. Smith’s team has found that nerve fibres (axons) can be injured in cases without a sustained loss of consciousness.

Research into axon damage is taking off, reports Smith, as people are beginning to realise its promise for potential diagnostic tests and treatments.

‘Many doctors have assumed that disturbances of mTBI calm down within 1–2 weeks, because this is when clinical symptoms usually disappear,’ says Henrik Zetterberg, professor of neurochemistry at the University of Gothenburg, Sweden. However, research suggests that it may take a lot longer, perhaps 30–45 days. And in some cases, disruption to the axons may continue for years. ‘This is particularly relevant to sports people who might return to playing too soon,’ says Zetterberg.

An axon is the long, slender projection of a nerve cell (neuron) that conducts electrical impulses. Normally stretchy, axons become brittle and can break when stretched very rapidly, such as when the head is hit hard and the brain rotates in the skull. Once destroyed, they can never regrow. Microtubules, which run like train tracks inside the axons, can also break. Smith explains: ‘This is a huge problem as they transport many different proteins. When they break, they dump their cargo and it piles up, leading to swelling at that point. The axons actually look like an inflated balloon. In severe cases, they swell up so much that they disconnect from the neurons.’

Another threat arises from the sodium ions that play a part in carrying electrical impulses down the nerve. ‘A sudden impact can wedge open the valve that controls the flow of sodium ions,’ explains Smith, ‘and they pour into the axons.’ In attempts to regulate the overload, the axons reverse the flow of calcium ions (necessary for cellular communication). ‘Instead of pumping them out, they bring them in, but too many can activate chemicals called proteases, which start to digest the inside of the axon.’

Further inflammation in the brain can be a result of the healing process. The body recruits cells – microglia – to remove debris, such as dead axons, as part of the ‘healing process’, explains Zetterberg, and these can also cause some swelling.

An axon is only a micron in diameter. This means diagnosing axon injury is challenging. In mild to moderate injury, patients’ brains may appear normal when imaged using techniques such as CT scanning. It’s only with microscopic examinations of the brain tissue from dead patients that doctors can see a multitude of swollen and disconnected axons.

Repetitive injuries

Some patients, who have been subjected to repetitive head injury, for example, American football players or boxers, can go on to develop CTE that is associated with neurodegenerative diseases. A form of TBI-induced early dementia was first reported in 1928 among professional boxers, years after their careers had ended. Initially termed dementia pugilistica, or punch-drunk syndrome, CTE is now thought to occur in 20% of former professional boxers.

More recently, this disorder has occurred in non-boxers exposed to varying degrees of repetitive head injury. But, at present, doctors can only confirm CTE by examining the brains of patients who have died.

For reasons that aren’t clear, repetitive injuries cause the tau protein found in axons to clump together, reports Daniel Daneshvar of the Center for the Study of Traumatic Encephalopathy at Boston University School of Medicine, US. One of tau’s jobs is to build an ordered microtubule network in axons but, in CET, the tau becomes ‘hyperphosphorylated’. This means that phosphorylation – a cell process where a phosphate group is added to a protein – occurs excessively. The tau is released from the microtubules and tangles together into misfolded clumps that can kill neurons.

Tau tangles are also found in AD: they build up in the fibrillary structures inside neurons. However, when Ann McKee’s group at Boston University School of Medicine, US, investigated the autopsy brains of 85 men with a history of repetitive mTBI, they found that while the structure of tau is the same as in AD,1 there is a difference in how it is distributed. ‘In the early stages of CTE, in the more mildly affected brains, we found that tau was clustered around small blood vessels in the depths of the brain’s folds and in the brain’s superficial layers,’ says Daneshvar. ‘This is very different to what is seen in Alzheimer’s patients. Later on, as CTE proceeds, tau tangles are found in regions of the brain responsible for memory and emotional regulation. The density of distribution and specific distribution in brain structures is completely different in CTE.’

Build-up of amyloid protein – also carried by the microtubules – is another hallmark of AD, but is only found in around 40% of CTE cases and occurs in a different, diffuse form, explains Daneshvar. ‘It’s possible that the overall mechanism in CTE is different to that in AD, even though the same proteins are present. In AD, the amyloid plaques start to build up earlier, which damages neurons and this causes tau to deposit. This would not explain what is happening in CTE, as we found that either no amyloid is present or only in very late stages of the disease progression.’

Significantly, it might not just be repetitive injuries that lead to tau build-up. Recently, a team from Boston University, led by Lee Goldstein, found that mice exposed to a single injury developed these tau clumps.

Detection and diagnosis

A major goal for doctors is to find accurate, non-invasive ways of diagnosing brain damage in living patients.

One promising avenue is the identification of biomarkers. Researchers use specific antibodies that bind to particular proteins normally found inside neurons. These antibodies can then flag up the presence of these proteins in spinal fluid taken from a patient. ‘This indicates that they have leaked out from damaged nerve cells,’ explains Zetterberg. ‘Several biomarkers of brain injury have been established in cerebrospinal fluid (CSF). One example is the test for total tau as a biomarker of injury to certain axons. We can measure for abnormal forms of tau not usually found in the CSF.’

Although Zetterberg says that tau in CSF is measured routinely in Sweden, biomarkers are not in common use in the US. Daneshvar, for example, considers the use of biomarkers to be still in the research stages. Although there are tests for tau markers in AD, they do not have the right specificity and sensitivity for CTE, he says, and may not pick up the changes that occur in CTE where tau has a different distribution.

However, research in the field of biomarkers for TBI and AD has advanced rapidly in the past two decades, he stresses. ‘Biomarker research is the key to better diagnosis,’ he says, ‘and biomarkers for tau are the most promising.’ But much work remains to be done to get useful, validated biomarkers that provide information about the long-term processes involved in CTE.

The main challenge for biomarker development is producing assays with enough sensitivity to detect proteins at very low concentrations, says Zetterberg. This is a particular problem for tests using blood samples where there are even lower concentrations of biomarkers than in spinal fluid. ‘This is challenging,’ he adds.

Researchers are also working on improving neuroimaging technologies to illuminate brain damage in living patients. Sergei Kirov at Georgia Regents University, US, has used two-photon laser scanning microscopy – a non-invasive type of fluorescent microscopy – to watch a mild traumatic brain injury play out in a living brain (of mice).2 ‘We saw every branch, every small wire and how it gets cut,’ Kirov says. ‘We saw how it destroys networks. It really goes downhill. It’s the first time we know of that someone has watched this type of minor injury play out over the course of 24 hours.’

Other imaging technologies include magnetic resonance imaging techniques, though these are complicated by the enormous amount of data collected. A variant of MRI – diffusion tensor imaging (DTI) – takes advantage of the molecular disarrangement that occurs in CTE. The technique can reveal axon damage in the white matter region of the brain, which is responsible for how the brain learns and functions – it coordinates communication between different regions of the brain. But accuracy and precision need to improve before DTI, and other MRI techniques, could be used for assessing CTE in living patients, says David Brody at Washington University, US.

Positron emission tomography, or PET scanning, is another imaging tool that shows promise for detecting CTE. PET scanning can map the location of particular molecules in the brain. Novel PET markers are being tested on patients with dementia, and could prove useful in CTE patients. For example, Hartmuth Kolb of Siemens in Culver City, California, US, has reported tests on two markers, T807 and T808. Both appear to bind specifically to tau in brains of dementia patients while healthy participants showed no such binding.

The links between dementia research and research into TBI are growing.3 Smith believes that a history of TBI is the number one environmental risk factor in developing AD. Current evidence indicates a possible ‘dose’ association between TBI and risk of neurodegenerative disease. So understanding what is going on in the brain in TBI may offer an opportunity for better understanding a wider range of neurodegenerative diseases, he says.


Currently, there is no treatment for brain trauma though many possible therapies have been investigated, says Smith. Relatively few of these have addressed axonal injury, even though it is one of the major features of brain trauma, but interest is growing, he reports.4 One such approach is the use of the immunosuppressant cyclosporin A (CsA). In animal models, CsA treatments before and after injury reduced the number of damaged axons. This action seems to be linked to CsA’s ability to block ion channels and prevent the chemical cascades that damage axons.

Other possible therapies include some chemotherapies, which work to stop cells dividing. According to Smith, in TBI, this action could stabilise microtubules in an axon, helping axons hold together and stay connected to their neurons.

Smith concludes: ‘As a doctor treating a patient, I know that this cascade of events is happening as I watch but I can’t do anything about it. I have no way of knowing, either, whether this will prove deleterious over time or not. One third of moderate to severe patients have these changes in their brain. Doctors need better ways of diagnosing the severity of an injury, predicting who is at risk from longer-term problems, and monitoring them to see if they develop symptoms. But, in the meantime, prevention is the best medicine.’


1 A McKee et al, Brain 2012; doi: 10.1093/brain/aws307
2 Kirov et al, Brain, 2013; doi: 10.1093/brain/awt026
3 D Smith et al, Nat. Rev. Neurol., 2013, 9, 211
4 John T. Povlishock et al, J. Neurotrauma, 2013, 30 (March), 1.

Maria Burke is a freelance science writer based in St Albans, UK

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