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Why CTE (Chronic Traumatic Encephalopathy) Can Currently Only Be Diagnosed Post-Mortem

Most often the outcome of repetitive head trauma, CTE belongs to a group of neurodegenerative diseases called taupathologies that include Alzheimer’s disease (AD), among many others. Taupathologies involve characteristic deposition of phosphorylated Tau protein in the CNS (Central nervous system) tissue. Answer to this question thus turns on the issue of whether CTE has a taupathy distinct from other diseases, and if yes, what such distinction consists of.

Currently, the CTE Center at Boston University led by Ann McKee is the leader in CTE research. According to their web-site’s FAQ (Frequently Asked Questions),

How is CTE diagnosed

At this time CTE can only be diagnosed after death by postmortem neuropathological analysis. Right now there is no known way to use MRI, CT, or other brain imaging methods to diagnose CTE. The CTE Center is actively conducting research aimed at learning how to diagnose CTE during life. For more information on this research, please visit Our Research ” CTE Center.’

Essentially, definitive CTE diagnosis is limited by

  • Symptom overlap. Considerable overlap of CTE’s currently defined symptoms with other neurodegenerative diseases. Current roster of CTE symptoms include Behavioral (aggression/agitation, apathy, delusions, depressions, impulsivity and suicidality), Cognitive (dementia, executive dysfunction, impaired attention and concentration, language difficulties, memory problems, visuospatial impairment), Motor symptoms (damage to cerebellar pyramidal systems, which display as ataxia, dysarthria, gait disturbances, parkinsonism, spasticity) (1; see table below from 2). These symptoms overlap with those of several other conditions such as AD, Frontotemporal dementia, Lewy body disease, Motor Neuron disease, to name just a few. This creates a problem for definitive diagnosis. Some examples of symptom overlap help explain the CTE diagnosis conundrum.
    • Amyloid deposition in Hippocampus with neurofibrilary tangles, predominating in the CA1 pyramidal neuron. Also seen in Alzheimer’s.
    • Prominent destruction of cerebellar dentate nucleus, with coiled bodies in oligodendrocytes and tufted astrocytes. Also seen in progressive supranuclear palsy.
    • Severe astrocyte tangles in striatum, pallidum, and cortical and subcortical structures. Also seen in globular glial atrophy.
  • Lack of definitive antemortem diagnostic methods. Current definitive diagnosis requires microscopic examination of brain tissue slices, i.e., post-mortem analysis.

As CTE is currently handicapped by such complications, the US National Institute of Neurological Disorders and Stroke decided in its most recent consensus statement that presence of histopathological features consistent with some other neurodegenerative disease excludes CTE as the sole diagnosis (3). Thus CTE remains a diagnosis of exclusion, i.e., all other medical or psychiatric diagnoses must be ruled out (2, 4, 5).

Kinds Of Studies And Technologies Needed To Diagnose CTE Antemortem: Prospective Clinical Trials And Biomarkers

A wide variety of imaging technologies have been used to examine CTE pathology antemortem. https://en.wikipedia.org/wiki/Ma… (MRI), Functional magnetic resonance imaging (fMRI), In vivo magnetic resonance spectroscopy (MRS) and Positron emission tomography (PET). However, results from such studies with small numbers of retired athletes have often suggested they lack adequate sensitivity (6) or are unclear (7).

PET is one of the more promising imaging technologies for CTE since at least one study shows signal difference between CTE and AD using this approach (8). In this study of 14 retired American football players and 24 patients with Alzheimer’s dementia, tau protein deposition in the retired football payers

  • Matched post-mortem patterns seen in confirmed CTE cases (9, 10).
  • Was distinct from those seen in AD.

Improving CTE diagnosis requires moving from post-mortem, i.e., retrospective, to prospective cohort studies (11). It’s promising that there is currently at least one ongoing PET clinical trial, Amyloid and Tauopathy PET Imaging in Acute and Chronic Traumatic Brain Injury.

CTE Biomarkers: Their Lack Is A Major Obstacle To Antemortem Diagnosis

A disease-associated oddity detectable in a biological fluid, a biomarker could be cellular, chemical or molecular, and biological fluid could be blood, cerebrospinal fluid (CSF), mucus, saliva, urine. Ideally, a biomarker’s essential features are ease of access and detection, and predictability.

  • Ease of access means the fluid sample should be easy to obtain with little discomfort, pain or risk to the patient.
  • Ease of detection means test should be cheap, rapid, reliable and reproducibly quantifiable.
  • Predictability means the test should be specific, sensitive and tightly associate with the disease, being rarely or never found in healthy people.

In fact, biomarkers are probably one of the buzziest of buzz words in biomedicine but very little of this buzz has yet translated to practical utility. A 2011 estimate found that while >150000 papers have been published on potential biomarkers for various diseases, <100 such biomarkers have been actually validated for clinical use (12). In the case of sports injury-related biomarkers, while ~11 biomarkers have been explored, none have as yet been clinically validated (13; also see figures below from 14). Just one indication among many that the path to antemortem CTE diagnosis is very steep indeed.

Among biomarkers for CTE,

  • Glial fibrillary acidic protein (GFAP) is one of the most promising (14). Almost exclusively expressed by Astrocyte (15), one study found GFAP was better able to predict intracranial injury on CT scans in patients with mild to moderate traumatic brain injury (TBI) (16).
  • Gamma-enolase, aka neuron-specific enolase, may be highly predictive of TBI (Traumatic Brain Injury) in children (17). However, being also expressed in erythrocytes limits its usefulness as a blood CTE biomarker. It may be more useful in CSF. Problem is that CSF-based diagnostics are much more cumbersome, invasive and risky.
  • While S100-B and GFAP have been extensively explored as blood or urine biomarkers, not so in CSF.

Improving CTE biomarker discovery requires

  • Better designed prospective clinical trials of larger numbers of patients.
  • Better sub-setting of patient populations in clinical trials to improve symptom and biomarker predictability.
  • Biomarker assay improvement using more specific reagents, e.g., more specific antibodies.
  • Simultaneous multiple biomarker discovery approach.


1. Pan, James, et al. “Sports-related brain injuries: connecting pathology to diagnosis.” Neurosurgical focus 40.4 (2016): E14. https://www.researchgate.net/pro…

2. Jordan, Barry D. “The clinical spectrum of sport-related traumatic brain injury.” Nature Reviews Neurology 9.4 (2013): 222-230. http://www.nature.com/nrneurol/j…

3. McKee, Ann C., et al. “The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.” Acta neuropathologica 131.1 (2016): 75-86. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

4. Victoroff, Jeff. “Traumatic encephalopathy: review and provisional research diagnostic criteria.” NeuroRehabilitation 32.2 (2013): 211-224.

5. Montenigro, Philip H., et al. “Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome.” Alzheimers Res Ther 6.5 (2014): 68. Alzheimer’s Research & Therapy

6. Casson, Ira R., et al. “Is there chronic brain damage in retired NFL players? Neuroradiology, neuropsychology, and neurology examinations of 45 retired players.” Sports Health: A Multidisciplinary Approach 6.5 (2014): 384-395.

7. Tremblay, Sara, et al. “Multimodal assessment of primary motor cortex integrity following sport concussion in asymptomatic athletes.” Clinical Neurophysiology 125.7 (2014): 1371-1379.

8. Small, Gary W., et al. “PET scanning of brain tau in retired national football league players: preliminary findings.” The American Journal of Geriatric Psychiatry 21.2 (2013): 138-144. https://www.researchgate.net/pro…

9. McKee, Ann C., et al. “The spectrum of disease in chronic traumatic encephalopathy.” Brain 136.1 (2013): 43-64. http://brain.oxfordjournals.org/…

10. Omalu, Bennet, et al. “Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes.” Neurosurgery 69.1 (2011): 173-183.

11. Davis, Gavin A., Rudolph J. Castellani, and Paul McCrory. “Neurodegeneration and sport.” Neurosurgery 76.6 (2015): 643-656. https://www.researchgate.net/pro…

12. Poste, George. “Bring on the biomarkers.” Nature 469.7329 (2011): 156-157.

13. Papa, Linda, et al. “Systematic review of clinical studies examining biomarkers of brain injury in athletes after sports-related concussion.” Journal of neurotrauma 32.10 (2015): 661-673.

14. Zetterberg, Henrik, Douglas H. Smith, and Kaj Blennow. “Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood.” Nature Reviews Neurology 9.4 (2013): 201-210. http://www.nature.com/nrneurol/j…

15. Olsson, Bob, et al. “Biomarker-based dissection of neurodegenerative diseases.” Progress in neurobiology 95.4 (2011): 520-534.

16. Papa, Linda, et al. “GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions.” Journal of neurotrauma 31.22 (2014): 1815-1822.

17. Kulbe, Jacqueline R., and James W. Geddes. “Current status of fluid biomarkers in mild traumatic brain injury.” Experimental neurology 275 (2016): 334-352.

Thanks for the R2A, Alecia Li Morgan.