The spectrum of disease in chronic traumatic encephalopathy.

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.

Procedural learning impairments identified via predictive saccades in chronic traumatic brain injury.

OBJECTIVE: To characterize integrity of fronto-striatal circuitry in chronic traumatic brain injury (TBI). BACKGROUND: Due to both direct and indirect effects, TBI is hypothesized to affect frontal and striatal function. On the basis of elegant animal, lesion, and neuroimaging literatures, oculomotor testing can provide a useful tool for in vivo assessments of neurophysiologic function. The predictive saccade paradigm in oculomotor function is well established to provide assessment of this fronto-striatal circuit. METHODS: Sixty patients with a history of chronic TBI completed 2 specific tests of oculomotor function, including a test of reflexive visually guided saccades to assess basic oculomotor function and a predictive saccade test to assess procedural learning. RESULTS: TBI (mild and moderate/severe) was associated with a decrease in rates of procedural learning, with degree of impairment increasing with injury severity. This was observed as a decrease in the proportion of anticipatory saccades (primary measure of learning). CONCLUSIONS: This abnormal oculomotor performance supports the hypothesis that TBI results in chronic impairment of frontal-striatal functions proportionally to injury severity and demonstrate that oculomotor testing is sensitive to all severities of closed-head injury.