Monday, February 05, 2018

Head Impact and Hyperphosphoralated Tau in Teens

We all agree that repeated blows to the head are bad for the brain. What we don't yet know is:
  • who will show lasting cognitive and behavioral impairments
  • who will show only transient sequelae (and for how long)
  • who will manifest long-term neurodegeneration
  • ...and by which specific cellular mechanism(s)

Adding to the confusion is the unclear terminology used to describe impact-related head injuries. Is a concussion the same as a mild traumatic brain injury (TBI)? Sharp and Jenkins say absolutely not, and contend that Concussion is confusing us all:
It is time to stop using the term concussion as it has no clear definition and no pathological meaning. This confusion is increasingly problematic as the management of ‘concussed’ individuals is a pressing concern. Historically, it has been used to describe patients briefly disabled following a head injury, with the assumption that this was due to a transient disorder of brain function without long-term sequelae. However, the symptoms of concussion are highly variable in duration, and can persist for many years with no reliable early predictors of outcome. Using vague terminology for post-traumatic problems leads to misconceptions and biases in the diagnostic process, producing uninterpretable science, poor clinical guidelines and confused policy. We propose that the term concussion should be avoided. Instead neurologists and other healthcare professionals should classify the severity of traumatic brain injury and then attempt to precisely diagnose the underlying cause of post-traumatic symptoms.

In an interview about the impressive mega-paper by Tagge, Fisher, Minaeva, et al. (2018), co-senior author Dr. Lee Goldstein also said no, but had a different interpretation:
When it comes to head injuries and CTE, Goldstein spoke of three categories that are being jumbled: concussions, TBI and CTE. Concussion, he says, is a syndrome defined “by consensus really every couple of years, based on the signs and symptoms of neurological syndrome, what happens after you get hit in the head. It’s nothing more than that, a syndrome...

A TBI is different. “it is an injury, an event,” he said. “It’s not a syndrome. It’s an event and it involves damage to tissue. If you don’t have a concussion, you can absolutely have brain injury and the converse is true.”
. . .

“So concussion may or may not be a TBI and equally important not having a concussion may or may not be associated with a TBI. A concussion doesn’t tell you anything about a TBI. Nor does it tell you anything about CTE.”

I think I'm even more confused now... you can have concussion (the syndrome) without an injury or an event?

But I'm really here to tell you about 8 post-mortem brains from teenage males who had engaged in contact sports. These were from Dr. Ann McKee's brain bank at BU, and were included in the paper along with extensive data from a mouse model (Tagge, Fisher, Minaeva, et al., 2018). Four brains were in the acute-subacute phase after mild closed-head impact injury and had previous diagnoses of concusion. The other 4 brains were control cases, including individuals who also had previous diagnoses of concussion. Let me repeat that. The controls had ALSO suffered head impact injuries at unknown (“not recent”) pre-mortem dates (>7 years prior in one case).

This amazing and important work was made possible by magnanimous donations from grieving parents. I am very sorry for the losses they have suffered.

Below is a summary of the cases.

Case 1
  • 18 year old multisport athlete American football (9 yrs), baseball, basketball, weight-lifting
  • history of 10 sports concussions
  • died by suicide (hanging) 4.2 months after a snowboarding accident with head injury
  • evidence of hyperphosphorylated tau protein 

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 1. (C) and (D) Hemosiderin-laden macrophages indicated by arrows, consistent with subacute head injury. (E)  microhemorrhage surrounded by neurites immunoreactive for phosphorylated tau protein (asterisks).

    Case 2
    • 18 year old multisport athlete American football (3 yrs), rugby, soccer, hockey
    • history of 4 concussions
    • one “severe concussion” 1 month before death, followed by “a second rugby-related head injury that resulted in sideline collapse and a 2-day hospitalization”
    • died a week later after weightlifting 
    • neuropathology not shown

    Case 3
    • 17 year old multisport athlete American football, lacrosse
    • history of 2 concussions, the second resulting in confusion and memory loss
    • small anterior cavum septum pellucidum (associated with CTE in other studies)
    • died by suicide (hanging) 2 days after second concussion

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 3. (F)-(H) amyloid precursor protein (APP)-immunostaining in the corpus callosum (arrows).

    Case 4
    • 17 year old American football player
    • history of 3 concussions (26 days, 2 days, 1 day before death)
    • final head injury was fatal, due to swelling and brain herniation
    • evidence of hyperphosphorylated tau protein
    • diagnosed with early-stage CTE

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 4. (O) Phosphorylated tau protein-containing neurofibrillary tangles, pretangles, and neurites in the sulcal depths of the cerebral cortex consistent with neuropathological diagnosis of early-stage CTE.

    CONTROLS none showed evidence of microvascular or axonal injury, astrocytosis, microgliosis, or phosphorylated tauopathy indicative of CTE or other neurodegenerative disease

    Case 5
    • 19 year old American football player 
    • history of concussion not reported (but can assume possible “blows to the head”)
    • died from multiple organ failure and cardiac arrest

    Case 6
    • 19 year old hockey player 
    • history of 6 concussions (time pre-mortem unknown)
    • died from cardiac arrhythmia

    Case 7
    • 17 year old American football player
    • history of concussion not reported (but can assume “blows to the head”)
    •  0.3-cm cavum septum pellucidum (consistent with impact injury)
    • died from oxycodone overdose (a factor neglected in previous studies)

    Case 8
    • 22 year old former American football player
    • history of 3 concussions (one with loss of consciousness) at least 7 years before death
    • history of bipolar disorder and 2 prior suicide attempts
    • died by suicide of unknown mechanism (also neglected in previous studies, but we don't know if asphyxiation was involved)

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 8. (K) Minimal GFAP-immunoreactive astrocytosis in white matter. (N) Few activated microglia in brainstem white matter [NOTE: not an acute-subacute case].

    The goal of this study was to look at pathology after acute-subacute head injury (e.g., astrocytosis, macrophages, and activated microglia). Only 2 of the cases showed hyperphosphorylated tau protein, which is characteristic of CTE. But in the media (e.g., It's not concussions that cause CTE. It's repeated hits), all of these changes have been conflated with CTE, a neurodegenerative condition that presumably develops over a longer time scale. Overall, the argument for a neat and tidy causal cascade is inconclusive in humans (in my view), because hyperphosphoralated tau was not observed in any of the controls, including those with significant histories of concussion. Or in Cases 2 and 3. Are we to assume, then, that concussions do not produce tauopathy in all cases? Is there a specific “dose” of head impact required? The mouse model is more precise in this realm, and those results seemed to drive the credulous headlines.

    Importantly, the authors admit that “Clearly, not every individual who sustains a head injury, even if repeated, will develop CTE brain pathology.” Conversely, CTE pathology can occur without having suffered a single blow to the head (Gao et al., 2017).

    Clearly, there's still a lot to learn.


    Gao AF, Ramsay D, Twose R, Rogaeva E, Tator C, Hazrati LN. (2017). Chronic traumatic encephalopathy-like neuropathological findings without a history of trauma. Int J Pathol Clin Res. 3:050.

    Sharp DJ, Jenkins PO. (2015). Concussion is confusing us all. Practical neurology 15(3):172-86.

    Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE. (2018). Concussion, microvascular injury,and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141: 422-458.

    Super Bowl Confetti Made Entirely From
    Shredded Concussion Studies

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