Rationale:
Hyperphosphorylated tau (pTau) has been increasingly interrogated as a biomarker for cognitive decline in epilepsy, as well as a mechanistic link between epilepsy and Alzheimer’s disease. Findings from tau immunohistochemistry in surgically resected tissues reveal a varying pTau burden (3.5 to 95%) in temporal lobe epilepsy (TLE), and inconsistent associations with pre- or postoperative language, memory and executive functions. Existing studies are limited by small samples with variable age ranges and epileptogenic pathologies. In this study, we explored the relationship of pTau burden, as measured in surgical specimens, with pre- and postoperative cognitive functions in a large, etiologically homogenous sample of TLE patients undergoing surgery.
Methods:
One hundred and six adult TLE patients (mean age= 35.5[18-36], mean age of onset=9.9[1-38], n=48 males) with histology-confirmed hippocampal sclerosis completed standardized neuropsychological assessments (Table 1) before, and 1-year after a unilateral temporal resection. Based on preoperative intellectual status, patients were divided into ‘decline’ and ‘stable’ groups where ‘decline’ was defined as > 9-point discrepancy between their premorbid and preoperative IQ scores. Clinically significant postoperative cognitive decline was defined as a change >= -1 standard deviation from preoperative performance.
pTau immunohistochemistry analysis with AT8 was carried out semi-quantitatively in temporal neocortex based on density of neuronal and dendritic labelling, and scored ranging from 0 (no AT8 staining) to 5 (high tau load).
Results:
pTau was present in 69/106 (59%, mean age:38.7; no tau mean age:31.8) cases. pTau load increased with increasing age (p=0.000).
Preoperatively cognitively stable patients (n=64, mean age=34.9) exhibited a higher pTau burden (median pTau= 2; p=0.014) relative to the decline group (n=42, mean age=36.5, mean pTau=0). Higher pTau burden associated with better preoperative verbal immediate (p=0.0006) and delayed recall scores (p=0.0014) regardless of side or surgery and preoperative intellectual status.
Higher pTau burden associated with a clinically significant decline in verbal learning p=0.035) in left-resected seizure free patients. Paradoxically, it also associated with an improvement in visual learning scores in left-resected patients with poor seizure outcomes (0.0297).
Conclusions:
Our clinico-pathological correlations support the contribution of pTau to cognitive functions, particularly to memory changes following surgery, replicating previous findings from our group (Tai et al., 2016). Our pre- and postoperative findings of better cognitive function in patients with increased tau load raise an intriguing question about a potentially stabilizing role of moderate tau load and distribution in chronic TLE.
Reference
Tai, X. Y. et al., (2016). Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: A study of temporal lobe resections. Brain, 139(9), 2441–2455.
Funding:
This work is supported by the Wellcome Trust Grant number: 221934/Z/20/Z.