Can a Diagnosis of Concussion Be Objective?

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb