Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy

Abstract

Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six post mortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE.

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…A recent analysis of abnormal phosphorylated tau (p-tau) deposition in samples from temporal cortex and adjacent white matter taken from patients with temporal lobe epilepsy (TLE) and chronic traumatic encephalopathy (CTE) has reported a similar pattern of pathological tau deposition in perivascular spaces in both conditions, suggesting similar underlying cerebrovascular pathology with abnormal perivascular p-tau accumulation as a potential mechanism [143]. Both TLE and CTE physiopathology involve neuronal death which likely initiates spillage of unbound tau protein into the extracellular space and, from there, to perivascular lining cells and perivascular spaces.…”

Do Patients with Temporal Lobe Epilepsy and Cognitive Decline Have Alzheimer's Disease or Chronic Traumatic Encephalopathy (CTE)?

“…The findings from this study raise intriguing questions about the presence of a possibly unique form of tauopathy associated with TLE while casting doubt on the proposed specificity of the pathological findings that have been attributed to AD and CTE (6,10).…”

The current state of biomarkers of mild traumatic brain injury

“…While human studies have been limited, extensive p-tau pathology throughout the brain has been observed in late-stage CTE, which is considered a sequelae of multiple mTBIs (1). However, the presence of p-tau alone may not be CTE specific, as patients with temporal lobe epilepsy also exhibit similar patterns of tau deposition in resected tissue (49). Pathological tau deposition in the brain is common among familial neurodegenerative disorders, including Alzheimer disease; therefore, p-tau alone has limitation as a mTBI-specific marker.…”