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

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Puvenna, Vikram, Engeler, Madeline, Banjara, Manoj, Brennan, Chanda, Schreiber, Peter, Dadas, Aaron, Bahrami, Ashkon, Solanki, Jesal +7 more·2016·Brain Research
DOI 10.1016/j.brainres.2015.11.007PMC PMC4853900
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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 postmortem 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.

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  • P-tau in perivascular, subpial, and periventricular regions has recently been described in postmortem brains of patients with ALS, temporal lobe epilepsy, and multiple system atrophy but no known history of participation in contact sports or neurotrauma.

    “P-tau in these regions has recently been described in the postmortem brains of patients who had ALS [31], temporal lobe epilepsy [32], and multiple system atrophy [33] but no known history of participation in contact sports or neurotrauma.”

    From The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features (2017) · cites this paper as [32]

    The Results and Discussion report perivascular and subpial phosphorylated tau in epileptic brain, and Methods (Epilepsy subjects) says the patients had no known history of traumatic brain injury. However, the epilepsy specimens were surgically resected, not postmortem, and the cited passages do not establish periventricular staining. ALS and multiple system atrophy are attached to other citations in the citing sentence. (LLM, conf=0.88)

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  • The presence of tau pathology in childhood or adolescent-onset epilepsies and in relatively younger temporal lobe epilepsy patient cohorts suggests a causal link between seizure activity and p-tau accumulation.

    “However, the presence of tau pathology in childhood or adolescent-onset epilepsies, such as Dravet syndrome, Nodding syndrome, Lafora disease, NPC, TSC, and ASD, and in relatively younger TLE patient cohorts (Puvenna et al., 2016; Smith et al., 2019; Gourmaud et al., 2020) suggest a causal link between seizure activity and p-tau accumulation.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Puvenna et al., 2016

    The Abstract (page not provided) reports phosphorylated tau in a relatively young temporal lobe epilepsy cohort, including a patient aged four months. But the Discussion (page not provided) says seizure history did not correlate with tau expression and leaves the mechanism unresolved. The paper does not examine the named syndromes or establish that seizure activity causes p-tau accumulation. (LLM, conf=0.87)

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  • In humans with chronic epilepsy, elevated p-tau is present in post-mortem as well as surgically resected tissue.

    “And in humans with chronic epilepsy, elevated p-tau is present in post-mortem (Thom et al., 2011) as well as surgically resected tissue (Puvenna et al., 2016; Tai et al., 2016; Liu C. et al., 2017; Prada Jardim et al., 2018; Smith et al., 2019; Gourmaud et al., 2020).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Puvenna et al., 2016

  • Observations of subpial bands formed by cortical p-tau depositions have been made across separate studies, providing evidence for a novel pattern of tau pathology in temporal lobe epilepsy that may result from seizure-induced reorganization of temporal lobe networks.

    “Interestingly, observations of subpial bands formed by cortical p-tau depositions have been made across separate studies (Puvenna et al., 2016; Tai et al., 2016; Smith et al., 2019), providing evidence for a novel pattern of tau pathology in TLE that may result from seizure-induced reorganization of temporal lobe networks (Tai et al., 2018).”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Puvenna et al., 2016

  • CTE pathology has been found in a small number of people with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases who have no known participation in collision or contact sports and no known exposure to repetitive neurotrauma.

    “In addition, it has been found in a small number of people with (1) substance abuse (24), (2) temporal lobe epilepsy (25), (3) amyotrophic lateral sclerosis (ALS) (26), (4) multiple system atrophy (22), and (5) other neurodegenerative diseases (23) who have no known participation in collision or contact sports and no known exposure to repetitive neurotrauma.”

    From Mild Chronic Traumatic Encephalopathy Neuropathology in People With No Known Participation in Contact Sports or History of Repetitive Neurotrauma (2019) · cites this paper as [25]

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Research works printed but not linked: 2

  1. [11]Goldstein LE Fisher AM Tagge CA Zhang XL Velisek L Sullivan JA Upreti C Kracht JM Ericsson M Wojnarowicz MW Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model Sci Transl Med 2012 5 16 4 134 134ra60 PMC3739428 22593173
  2. [12]McKee AC Cantu RC Nowinski CJ Hedley-Whyte ET Gavett BE Budson AE Santini VE Lee HS Kubilus CA Stern RA Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury J Neuropathol Exp Neurol 2009 7 68 7 709 35 19535999 PMC2945234

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Authors
Puvenna, V., Engeler, M., Banjara, M., Brennan, C., Schreiber, P., Dadas, A., Bahrami, A., Solanki, J., Bandyopadhyay, A., Morris, J. K., Bernick, C., Ghosh, C., Rapp, E., Bazarian, J. J., & Janigro, D.
Affiliations
  • Cleveland Clinic Lerner College of Medicine (US)
  • Brandeis University (US)
  • University of Pittsburgh (US)
  • The Ohio State University (US)
  • Baldwin Wallace University (US)
  • Emory University (US)
  • Cleveland Clinic (US)
  • University of Rochester Medicine (US)
Corresponding author
Janigro, Damir
ORCID
Venue
Brain Research
Publisher
Elsevier BV
Published
2016-01
Volume
1630
Pages
225-240
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/j.brainres.2015.11.007
PMC
PMC4853900
OpenAlex
W2140341262
Cited by
144
References
21
Citations by year
2026: 7 · 2025: 5 · 2024: 7 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 11 · 2019: 27 · 2018: 16 · 2017: 17 · 2016: 7 · 2014: 1
FWCI
10.45
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Boston University Center
Topics
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
phosphorylated tau, chronic traumatic encephalopathy, temporal lobe epilepsy, repetitive traumatic brain injury, tau pathology, tau tangles, limbic system, postmortem brain
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Brain, Child, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Epilepsy, Female, Humans, Immunohistochemistry, Infant, Male, Middle Aged, Phosphorylation, tau Proteins, Brain Injury, Chronic, Young Adult

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