Research Reports - The spectrum of disease in chronic traumatic encephalopathy

Brain. 2012 Dec 2

McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall
G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin
BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall
NW, Cantu RC

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a
consequence of repetitive mild traumatic brain injury. We analysed post-mortem
brains obtained from a cohort of 85 subjects with histories of repetitive mild
traumatic brain injury and found evidence of chronic traumatic encephalopathy in
68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years),
including 64 athletes, 21 military veterans (86% of whom were also athletes) and
one individual who engaged in self-injurious head banging behaviour. Eighteen
age- and gender-matched individuals without a history of repetitive mild
traumatic brain injury served as control subjects. In chronic traumatic
encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in
severity from focal perivascular epicentres of neurofibrillary tangles in the
frontal neocortex to severe tauopathy affecting widespread brain regions,
including the medial temporal lobe, thereby allowing a progressive staging of
pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were
found in deep cortex and subcortical white matter at all stages of chronic
traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions
and neurites were also found in 85% of cases, ranging from focal pathology in
stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage
I chronic traumatic encephalopathy included headache and loss of attention and
concentration. Additional symptoms in stage II included depression, explosivity
and short-term memory loss. In stage III, executive dysfunction and cognitive
impairment were found, and in stage IV, dementia, word-finding difficulty and
aggression were characteristic. Data on athletic exposure were available for 34
American football players; the stage of chronic traumatic encephalopathy
correlated with increased duration of football play, survival after football and
age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases
(63%); eight were also diagnosed with motor neuron disease (12%), seven with
Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with
frontotemporal lobar degeneration (6%). There is an ordered and predictable
progression of hyperphosphorylated tau abnormalities through the nervous system
in chronic traumatic encephalopathy that occurs in conjunction with widespread
axonal disruption and loss. The frequent association of chronic traumatic
encephalopathy with other neurodegenerative disorders suggests that repetitive
brain trauma and hyperphosphorylated tau protein deposition promote the
accumulation of other abnormally aggregated proteins including TAR DNA-binding
protein 43, amyloid beta protein and alpha-synuclein.

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