Tau deposition in young adults with drug‐resistant focal epilepsy

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract Objective: To evaluate the presence of tau deposition and pathologic features of chronic traumatic encephalopathy (CTE) in young adult patients treated with focal cortical resections for drug-resistant epilepsy. Methods: Sixty consecutive patients who had undergone surgical treatment for drugresistant focal epilepsy between 18 and 45 years of age were identified (2010-2017).Medical records were reviewed to determine clinical factors, including history of head trauma, age at seizure onset, age at surgical resection, seizure type(s) and frequency, imaging findings, and surgical outcome. All formalin-fixed, paraffin-embedded blocks from the surgical specimens from each subject were sectioned and stained with hematoxylin and eosin and antibodies to tau (Thermo Fisher Scientific Clone AT8), and examined blindly for tau pathology, including lesions characteristic of CTE. Results: The median age at resection was 29.5 years (range = 19-45). A history of head trauma was reported in 19 patients. Although none of the patients had pathological findings characteristic of CTE, 23 patients (38%) demonstrated tau-immunoreactive lesions, including neurites, neurofibrillary pretangles, neurofibrillary tangles, subpial tau, and/or glial tau. In 4 of the 23 patients (7% of the cohort; 17% of those with tau pathology), substantial tau burden was identified. Three of these 4 patients had no significant history of head trauma; 1 patient had multiple sports-related concussions. No specific clinical factors correlated with the presence of tau pathology. Significance: Tau-immunoreactive lesions were found in 38% of 60 patients who underwent a focal cortical resection for drug-resistant focal epilepsy. Diagnostic features of CTE were not detected in any patient; however, the pathological evaluation for CTE was limited to a surgical specimen. The prominent and excessive tau deposition in 23 patients (38%) is abnormal in this age group and warrants further investigation. K E Y W O R D Schronic traumatic encephalopathy, epilepsy surgery, neuropathology | 2399 SMITH eT al.

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

“…This association was based on evidence that epileptic seizures and cognitive deficits are frequently reported in patients with Alzheimer's Disease (AD), the most common form of tauopathies (Amatniek et al, 2006;Palop and Mucke, 2009). Analysis of surgically resected epileptic brains revealed similar pathologies to those observed in AD including abnormally phosphorylated tau and increased amyloid precursor protein (APP) (Thom et al, 2011;Tai et al, 2016;Smith et al, 2019;Gourmaud et al, 2020). In addition to tau pathology, increased Fyn expression was evident in AD brains (Shirazi and Wood, 1993;Ho et al, 2005).…”

Targeted Reducing of Tauopathy Alleviates Epileptic Seizures and Spatial Memory Impairment in an Optogenetically Inducible Mouse Model of Epilepsy

“…Hyperphosphorylation of tau hinders its degradation, thus leading to the aggregation of tau and forming of neurotoxic paired helices ( Sadqi et al, 2002 ). Abnormal accumulation of hyperphosphorylated tau in the hippocampus or appearance of neuropil threads and NFTs in the resected epileptogenic temporal lobe has been reported in a majority of epilepsy patients ( Tai et al, 2016 ; Smith et al, 2019 ). Consistently, we found that repeated induction of seizures prominently elevated phosphorylated and total tau levels in the cortex and hippocampus.…”

“…Hyperphosphorylation and intracellular accumulation of tau protein dysregulate microtubule assembly and aggravate the formation of neurofibrillary tangles, thus remodeling neuronal synapses and exacerbating cognitive decline in a collection of diseases named tauopathies, including Alzheimer disease (AD; Wang et al, 2014 ; Wang and Mandelkow, 2016 ; Yang and Wang, 2018 ). Recent studies also revealed prominent accumulation of hyperphosphorylated tau in the brain of temporal lobe epilepsy patients ( Tai et al, 2016 ; Smith et al, 2019 ). Given that epilepsy and early stage AD share many neurological characters and psychiatric symptoms ( Kanner, 2009 ; Cheng et al, 2015 ; Zarea et al, 2016 ), we wonder whether tau pathology also contributes to the cognitive deficits in epilepsy.…”

Deep Brain Stimulation for Alzheimer’s Disease: Tackling Circuit Dysfunction

“…In addition, patterns of hippocampal atrophy and connectivity observed in AD mimic those seen in mesial temporal epilepsy (61,72,138–140). Hyperphosphorylated tau has been found even in young patients with refractive focal epilepsy and correlated with cognitive decline, suggesting that seizures may in turn contribute to progressive AD pathology (141,142).…”