TBI history

A comprehensive history of head impact exposure includes consideration of:

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  Moderate to severe traumatic brain injury (TBI)

  
  
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  Single or isolated instances of mild TBI (mTBI), often called concussion

  
  
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  Repetitive subclinical head impact exposure, also known as subconcussive blows , which refers to head impacts presumably resulting in physiological disruption that do not manifest symptomatically; such impacts are common in populations playing collision sports (most notably boxing and American football), engaging in certain military activities, and exposed to frequent assaults (e.g., domestic violence)

Confounding factors

Both methodological and person-specific factors complicate the current understanding of the relationship between brain trauma and neurodegenerative disease or dementia.

Such factors include:

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  Differing definitions of outcomes: specific disease states (CTE, Alzheimer disease) versus a clinical syndrome (mild cognitive impairment, dementia)

  
  
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  Differing methods for defining brain trauma or neurological outcomes: severity indicators, subjective report, medical records, etc.

  
  
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  Age when exposed to brain trauma: e.g., youth, adolescence, or young adulthood versus middle-aged or elderly

  
  
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  Uncertain contribution of non-brain trauma factors to subsequent development of neurodegenerative disease or dementia, for example, genetic risk, psychiatric disorders, substance use, sociodemographics, and cognitive reserve indicators

Research controversies

Autopsy findings in patients deceased shortly after severe TBI indicate neuropathologic features that overlap neurodegenerative diseases such Alzheimer disease (Johnson et al., 2010). However, the mechanisms translating acute brain injury to a progressive and neurodegenerative process are poorly characterized. Mild TBI research is notably inconsistent both with findings and methodology. Variable definitions for mTBI history, time since injury, operationalization of outcomes (e.g., specific diseases versus dementia syndromes), and follow-up duration contribute to mixed and contradictory results (Asken & Bauer, 2018). Studies that show increased risk after mTBI typically report relative risk and hazard ratios between 1.5 and 2.0, whereas others have found no such relationship. Importantly, studies have shown that the degree of risk specifically associated with mTBI history typically drops to clinically negligible magnitudes when factoring in non-TBI risk factors for poor later-life neurologic health. These factors also often convey a stronger risk for neurodegenerative disease/dementia than mTBI when compared directly.

Mechanistic theories

Mechanistic theories about the implications of single TBI events on later neurodegenerative processes may not directly overlap with the hypothesized links between repetitive mild/subclinical events and later neurodegeneration. The attention paid specifically to CTE stems from case series studying individuals with years of exposure to both multiple mTBIs and repetitive subclinical head impacts (Bieniek et al., 2015, Mez et al., 2017). A recent consensus meeting established general—but not universal—agreement that the pathognomonic CTE lesion is perivascular accumulation of hyperphosphorylated tau in an irregular dotlike pattern affecting neurons, astrocytes, and cell processes preferentially at the depths of cortical sulci (McKee et al., 2016). Like most neurodegenerative diseases, CTE is often a mixed pathology (Mez et al., 2017; Stein et al., 2015). The largest CTE case series to date, including 177 retired professional football players, showed that 61% of cases had diffuse or neuritic Aβ plaques, 48% had TDP-43, and 24% had α-synuclein (Mez et al., 2017).

Summary

Brain trauma, however defined, may increase relative risk for CTE or other neurodegenerative diseases, but accurate quantification of risk remains unclear because of unknown CTE prevalence and incidence rates. There are currently no validated CTE biomarker profiles. The presumed regional specificity of tau deposits in CTE suggests advanced neuroimaging such as positron emission tomography (PET-tau) holds promise, but fluid biomarkers may struggle to adequately differentiate CTE from other neurodegenerative tauopathies like frontotemporal lobar degeneration (FTLD) and Alzheimer disease (Elahi & Miller, 2017).

Further, the clinical manifestation of CTE is complicated by the presence of non–brain trauma factors (see earlier) common among at-risk populations that directly and indirectly affect cognition, behavior, and mood (Asken et al., 2016, Asken et al., 2017). Ongoing longitudinal studies and clinical trials enrolling more diverse cohorts and using advanced assessment methods (e.g., advanced brain imaging, fluid biomarkers, and comprehensive neuropsychological testing) are likely to advance rapidly our understanding of CTE, its symptoms, and individual-level risk factors for poor neurological outcomes of brain trauma exposure.

Review questions

• 1.
  

  According to the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Biomedical Imaging and Bioengineering (NIBIB) provisional diagnostic criteria, what is the pathognomonic neuropathologic sign of chronic traumatic encephalopathy (CTE)?

  
  
  
  
  • a.
    

    Intracellular phosphorylated tau in the form of neurofibrillary tangles and neuropil threads deposited in the pre-α layer of transentorhinal cortex; extracellular Aβ plaques in neocortical regions

    
    
  • b.
    

    Perivascular accumulation of hyperphosphorylated tau in an irregular dotlike pattern affecting neurons, astrocytes, and cell processes preferentially at the depths of cortical sulci

    
    
  • c.
    

    α-Synuclein inclusions within neuronal perikarya and neuronal processes along with pigment loss in the substantia nigra

    
    
  • d.
    

    Degeneration of cortical and subcortical structures within frontal and temporal regions typically related to tau and/or TDP-43 pathology

  
  
  
  
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  CTE is predominantly characterized as a tauopathy but often presents as mixed pathology at autopsy. Which of these most accurately shows the relative frequency of other neurodegenerative proteins, from most to least frequent, within current CTE case series?

  
  
  
  
  • a.
    

    Aβ > TDP-43 > α-synuclein

    
    
  • b.
    

    α-synuclein > TDP-43 > Aβ

    
    
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    Aβ > α-synuclein > TDP-43

    
    
  • d.
    

    TDP-43 > α-synuclein > Aβ

  
  
  
  
• 3.
  

  The overwhelming majority of CTE cases are individuals with past exposure to head trauma. What is the strongest identified risk factor for developing CTE pathology?

  
  
  
  
  • a.
    

    Single or isolated instances of mild traumatic brain injury (mTBI) during childhood and adolescence

    
    
  • b.
    

    A moderate to severe traumatic brain injury (TBI) at any point in the lifespan

    
    
  • c.
    

    Multiple concussions/mTBIs occurring within a “window of vulnerability” (i.e., while still recovering from prior concussion/mTBI)

    
    
  • d.
    

    Extensive exposure to both mTBIs and repetitive subclinical head impacts (i.e., “subconcussive” blows) throughout life

  
  

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• 4.
  

  Many studies have investigated risk for incident neurodegenerative disease and/or dementia after single or isolated mTBI events. Which statement best summarizes this relationship?

  
  
  
  
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    Mixed findings; some research shows approximately 2.0 times greater risk for incident neurodegenerative disease/dementia, although this diminishes significantly when accounting for non-TBI risk factors such as psychiatric disorders, substance use, and education level

    
    
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    Clear and consistent findings of at least 2.0 times greater risk for incident neurodegenerative disease/dementia, although this diminishes significantly when accounting for non-TBI factors

    
    
  • c.
    

    Clear and consistent findings of at least 2.0 times greater risk for incident neurodegenerative disease/dementia; this relative risk is robust against effects of non-TBI risk factors

    
    
  • d.
    

    Mixed findings; some research shows approximately 5.0 times greater risk for incident neurodegenerative disease/dementia, although this diminishes significantly when accounting for non-TBI risk factors

  
  
  
  
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  Like other neurodegenerative diseases, CTE can only be diagnosed definitively by autopsy. Which of these biomarker/clinical profile pairs most reliably and validly predict CTE pathology antemortem?

  
  
  
  
  • a.
    

    ↑ p-tau, ↑ total tau, ↓ Aβ42:Aβ40 ratio within cerebrospinal fluid (CSF): early episodic memory loss, word-finding difficulties, semantic deficits

    
    
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    Nonspecific ↑ total tau in CSF: left/right confusion, acalculia, finger agnosia, agraphia

    
    
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    ↑ tau tracer uptake on positron emission tomography (PET-tau), reduced midbrain/pons ratio on sagittal magnetic resonance imaging (MRI): axial rigidity, procerus sign, supranuclear gaze palsy

    
    
  • d.
    

    Anterior and inferior temporal lobe atrophy on MRI, nonspecific ↑ total tau in CSF: anomia, ↓ single-word comprehension, ↓ confrontation naming, surface dyslexia

    
    
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    There is no reliable, valid in vivo biomarker or clinical profile predictive of CTE pathology

  
  
  
  
• 6.
  

  A man in his late 70s presents with a 4-year history of gradually progressing cognitive decline, impulsivity, and aggression. History is notable for several years participating in boxing and American football, although details of frank mTBI events are murky. Testing reveals very low scores on memory and executive function assessments. Computed tomography showed mild, nonspecific atrophy and cavum septum pellucidum. PET-Aβ imaging was negative (standard uptake value ratio [SUVR] = 1.0). Which is the most likely primary etiology of the gentleman’s cognitive and behavioral complaints?

  
  
  
  
  • a.
    

    Alzheimer’s disease

    
    
  • b.
    

    Scrapie prion protein (Creutzfeldt-Jakob disease)

    
    
  • c.
    

    CTE

    
    
  • d.
    

    Lewy body disease