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Hyperphosphorylated Tau and Cognition in Epilepsy

A peer-reviewed version of this preprint was published in:
Journal of Clinical Medicine 2025, 14(2), 514. https://doi.org/10.3390/jcm14020514

Submitted:

15 November 2024

Posted:

19 November 2024

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Abstract
In light of the current interest in the bidirectional relationship between epilepsy and dementia, primary attention is currently focused on the role of hyperphosphorylated tau (pTau) in cognition in epilepsy. Synthesizing available data from studies investigating pTau burden in surgical biopsy specimens from patients with temporal lobe epilepsy, the prevalence of pTau across five studies with a total number of 142 patients ranges from 3.5% to 95%. Findings also varied with regard to the location of pTau in the hippocampus and/or temporal cortex. Two of five studies (40%) demonstrated an inverse relationship between pTau burden and cognitive performance, one study with regard to executive functions and the other with regard to naming and verbal short-term memory. This is partly unexpected since executive functions and verbal short-term memory depend less on temporal than extratemporal fronto-parietal networks. The only longitudinal study found a significant link between pTau and cognitive decline in verbal learning and memory and in part also in naming from pre- to postoperative and from three to 12 months postoperative. Given the heterogeneity of the study cohorts, the neuropsychological and neuropathological methods and findings, no clear picture emerges regarding the association between pTau and cognition in temporal lobe epilepsy. This could in part be expected due to the multifactorial etiology of cognitive impairment in epilepsy, including the active epilepsy, the underlying and sometimes dynamic pathology, and anti-seizure medication. Some of these factors may affect pTau expression. Further research should investigate pTau longitudinally and noninvasively on a whole-brain level, using standardized, targeted neuropsychological outcome measures, while controlling for age and other factors that may influence cognitive trajectories in epilepsy.
Keywords: 
epilepsy
;  
seizures
;  
tau
;  
hyperphosphorylation
;  
neurodegeneration
;  
hippocampus
;  
temporal cortex
;  
neuropsychology cognition
;  
dementia
Subject: 
Medicine and Pharmacology  -   Neuroscience and Neurology
A current topic of interest in the field of epilepsy is the role of hyperphosphorylated tau (pTau) for neuronal damage, compromise of neuronal network function, and the clinical manifestation of cognitive impairment. Tau is a protein with a crucial role in stabilizing microtubules. Hyperphosphorylation of tau (in form of neuropil threads, pre-tangles, or neurofibrillary tangles) leads to a loss of this function causing a collapse of the axonal microtubules. By this, pTau may disrupt axonal transport and finally lead to neuronal dysfunction. In this focused review, we present studies on the effects of pTau on cognition in people with epilepsy (PWE).
The first relevant study by Tai et al. from the UK, published in 2016, was based on neuropathological examinations of specimens from 33 patients who had undergone epilepsy surgery for mesial temporal lobe epilepsy [1]. The authors hypothesized that pTau burden would be correlated with cognitive decline in temporal lobe epilepsy. The age at surgery ranged from 50 to 65 years with a mean of 53.6 years. The average age at epilepsy onset was 14.7 years (no range reported). All patients had hippocampal sclerosis according to the neuropathological examination. PTau was identified via immunohistochemistry (AT8) and quantified applying a modified tau score devised specifically for analysis of specimens from anterior temporal lobe resections. The prevalence of pTau (including neuropil threads, pre-tangles, and neurofibrillary tangles) was very high, i.e. 31/33 cases (94%). However, there was a relative sparing of the sclerotic hippocampus. Cognitive data (verbal and visual learning and memory, naming and phonemic and semantic fluency; the employed tests are listed in Table 3) gathered before as well as 3 and 12 months after surgery were available in a subgroup of 21 patients (64%). In addition, intelligence was measured before surgery. The analysis focused on cognitive changes from pre- to 12 months postoperative and from 3 to 12 months postoperative. First of all, there was no significant association between pTau burden and presurgical neuropsychological performance. At the 12-month-follow-up a significant deterioration in verbal memory and a discrete improvement in visual memory were observed compared to the presurgical status. There was a significant association between this cognitive change and the pTau burden. The higher the latter, the greater was the cognitive decline. This is especially valid for verbal learning (r = -.63) followed by naming performance (r = -.50) and verbal memory (r = -.44). When analyzing the cognitive change from the early to the later postoperative follow-up the same association was solely found for verbal learning (r = -.54). The authors concluded that pTau contributes to an accelerated decline of cognitive functions in epilepsy.
Gourmaud and colleagues [2] from the US also investigated tissue gathered from anterior temporal lobe resections from a much younger cohort of 19 patients with phamacoresistant epilepsy. The age at surgery ranged from 10-56 years with an average of 29 years. The mean age at epilepsy onset was 14.8 years (calculated based on Supplementary Table 1), ranging from 1-36 years. The most frequent primary pathology was hippocampal sclerosis (63.2%), few of them with dual pathology (including FCD type IIa, dysembryoplastic neuroepithelial tumour, periventricular heterotopia), and 1 patient had leptomeningeal vascular malformation. Besides presence of Aβ in hippocampal tissue, immunohistochemical analysis revealed an increased expression of pTau in both hippocampus and temporal neocortex. The cognitive analysis focused on 14 adult patients (74%) and the presurgical assessment of Intelligence (Wechsler Adult Intelligence Scale IV, WAIS IV), executive functions (digit span backward test; Trail Making Test B, TMT-B), verbal (California Verbal Learning Test II, CVLT-II) and visuospatial long-term memory (BVMT-R), visuospatial functions (Brief Visuospatial Memory Test Revised, BFRT; Rey-Osterrieth Complex Figure Test, ROCF), language (naming subtest of Neuropsychological Assessment Battery, NAB), and dexterity (Grooved Pegboard Test, GPT). Both total and pTau (as well as elements of the amyloid signalling pathway) correlated with deficits in executive functions (processing speed efficiency, verbal working memory). The authors conclude that amyloid and tau-associated neurodegeneration similar to Alzheimer’s disease may contribute to cognitive impairment in patients with drug-refractory temporal lobe epilepsy.
Table 1. Major study characteristics.
Table 1. Major study characteristics.
First author Year of publication Country N Age, years (range) Age at epilepsy onset, years (range) Controls
Tai 2016 UK 33 54 (50-65) 15 (n.a.) age-matched population controls from a post-mortem series
Gourmaud 2020 US 19 29 (10-56) 15 (1-36) 22 neurologically normal and 9 Alzheimer´s disease autopsy cases
Silva 2021 AUS 56 34 (20-68) 15 (0-56) -
Toscano 2023 US/BR 22 42 (30-58) 4 (0-13) 20 hippocampi of neurologically normal autopsy cases
Aroor 2023 US 12 43 (24-67) 19 (1-66) -
n.a., not available
Table 2. Neuropathological methods and findings.
Table 2. Neuropathological methods and findings.
First author Year of publication N Hippocampal sclerosis Method (pTau) Prevalence of pTau Form of pTau Location Other findings
Tai 2016 33 100% IHC (AT8) 94% NT + PT + NFT Mostly TC; relative sparing of HC Aβ plaques in 15%
Gourmaud 2020 19 63% IHC (AT8, clone Tau5) n.a. n.a. TC + HC APP deposits in 3/11 (27%)
Silva 2021 56 52% IHC (AT8) 3.5% NFT TC, not HC Aβ plaques in 7%
Toscano 2023 22 100% IHC + MA 95% NT + PT + NFT HC (TC n.a.) Aβ deposits absent
Aroor 2023 12 n.a. IHC + IA 50% NT + NFT TC (HC not analyzed) Aβ deposits in 67%
n.a., not available; APP, amyloid precursor protein; HC, hippocampus; HS, hippocampal sclerosis; IHC, immunohistochemistry; IA, immunoassays; MA, morphometric analyses; NFT, neurofibrillary tangles; NT, neuropil threads; PT, pre-tangles; pTau, hyperphosphorylated tau; TC, temporal cortex
Table 3. Neuropsychological methods and findings.
Table 3. Neuropsychological methods and findings.
First author Year of publication N Assessed cognitive functions and tests Relationships between pTau and neuropsychological performance
Tai 2016 21/33 (64%) Intelligence (WAIS), verbal and visual learning and long-term memory (AMIPB or BIMPB), naming (GNT) and phonemic, semantic fluency There was no significant association between pTau and presurgical neuropsychological performance. Higher pTau burden was inversely correlated with cognitive decline from pre- to 12 months postoperative (verbal learning (r = -.63) and memory (r = -.44) and naming (r = -.50)) as well as from 3 months to 12-months postoperative (verbal learning (r = -.54)).
Gourmaud 2020 14/19 (74%) Intelligence (WAIS IV), executive function (digit span backward test, TMT-B), verbal (CVLT-II) and visuospatial long-term memory (BVMT-R), visuospatial functions (BFRT, ROCF), language (naming subtest of NAB), and dexterity (GPT) Both total and pTau burden inversely correlated with presurgical deficits in executive functions (processing speed efficiency (r = -.78), verbal working memory (r = -.89)).
Silva 2021 31-52/56
(55-93%)		 verbal learning and long-term memory (RAVLT, VPA from WMS-R), visual long-term memory (ROCF) No significant correlation between pTau and presurgical memory performance.
Toscano 2023 22/22
(100%)		 verbal short-term memory (subtest of WAIS), verbal (LM I and II of WMS) and visual long-term memory (VR I and II of WMS), and confrontative naming (BNT) A higher pTau burden was associated with deficits in confrontative naming and verbal memory span. The latter relationship was confirmed by a multivariate model adjusted for age, sex, education, seizure frequency, and type of hippocampal sclerosis.
Aroor 2023 8/12
(67%)		 Intelligence (abbreviated WAIS) No significant correlation between pTau levels at two different sites (Thr181 and Thr205) and intelligence. However, the non-significant positive (!) correlation coefficient was large at site Thr181 (r = .54, p = 0.16).
AMIPB, Adult Memory and Information Processing Battery; BFRT, Benton Facial Recognition Test; BIMPB, BIRT memory and information processing battery; BNT, Boston Naming Test; BVMT-R, Brief Visuospatial Memory Test Revised; CVLT-II, California Verbal Learning Test II; GNT, Graded Naming Test; GPT, Grooved Pegboard Test; LM, Logical Memory; pTau, hyperphosphorylated tau; NAB, Neuropsychological Assessment Battery; RAVLT, Rey Auditory Verbal Learning Test; ROCF, Rey-Osterrieth Complex Figure Test; TMT-B, Trail Making Test B, VPA, Verbal Pair Associates; WAIS, Wechsler Adult Intelligence Scale; WMS(-R), Wechsler Memory Scale (Revised).
Silva et al. [3] from Australia analyzed resective specimens from 56 patients who had undergone epilepsy surgery for drug-resistant temporal lobe epilepsy. Age at anterior temporal lobectomy ranged from 20-68 years with a median of 34 years. The age at epilepsy onset varied from 0-56 years (median: 15). Histology revealed hippocampal sclerosis in the majority of patients (51.9%). The prevalence of pTau (3.5%) and Aβ plaques (7%) was low. The presurgical neuropsychological assessment included measures of verbal (Rey Auditory Verbal Learning Test (RAVLT), Verbal Pair Associates (VPA) subtest from Wechsler Memory Scale Revised (WMS-R) and visual memory (Rey- Osterrieth Complex Figure Test (ROCF)). Depending on the test, cognitive data was available from 31-52 patients. Patients with Aβ plaques scored worse in the more demanding part of the VPA subtest. There were no other significant associations between presurgical memory performance and Aβ plaques or pTau. Given the low prevalence of pTau and Aβ plaques, the authors state that “it is unlikely that cognitive impairment in TLE is driven by the same mechanisms as in Alzheimer disease” (p. 3058).
The study by Toscano and colleagues [4] from the US and Brazil in 2023 determined pTau in the resected hippocampal formation of 22 patients who had undergone epilepsy surgery for mesial temporal lobe epilepsy. The age ranged from 30-58 years with a mean of 41.8 years. The age at epilepsy onset was rather early with an average of 4.3 years (range: 0-13 years). In all patients, hippocampal sclerosis was diagnosed via histology. Compared to the non-sclerotic hippocampi of 20 autopsy controls of comparable age, pTau burden was significantly higher in patients with epilepsy. Among the patients, those with hippocampal sclerosis type 2 had a higher pTau burden than those with type 1. Aβ deposits were not observed. The presurgical neuropsychological examination which was performed in all included 22 patients focused on verbal short-term memory (Digit Span of the Wechsler Adult Intelligence Scale (WAIS)), verbal and visual long-term memory (Logical Memory I and II, Visual Reproduction I and II of the Wechsler Memory Scale (WMS)), and confrontative naming (Boston Naming Test (BNT)). A higher pTau burden was associated with deficits in confrontative naming and verbal memory span. In a multivariate model adjusted for age, sex, education, seizure frequency, and type of hippocampal sclerosis, only the verbal memory span showed still an association with pTau burden. The authors conclude that tau pathology may be a potential contributor to cognitive impairment in mesial temporal lobe epilepsy.
The most recent study that analyzed surgical biopsy specimens was published in 2023 by Aroor et al. [5] from the US. The authors determined pTau levels (along with Aβ) in the resective specimens from temporal lobe resections performed in 12 patients with drug-resistant epilepsy. The age ranged from 24-67 years with an average of 42.5 years. The mean age at epilepsy onset (calculated based on Table 1) was 18.9 years (range: 1-66). The actual primary pathologies were unfortunately only reported for two patients (FCD type Ib and FCD type IIIa), for the others only presumptive MRI findings are listed including mesial temporal sclerosis, cortical dysplasia, heterotopia, possible neoplasm and three non-specific cases. Immunohistology and enzyme-linked immunoassays indicated a robust presence of pTau in form of neuropil threads or neurofibrillary tangles (as well as Aβ deposits). Cognitive data was limited to the presurgical results of an abbreviated Wechsler intelligence test which were only available for 8 of the 12 patients (67%). Correlation analyses revealed no significant associations between pTau levels at two different sites (Thr181 and Thr205) and intelligence. However, the non-significant positive (!) correlation coefficient was large at site Thr181 (r = .54, p = 0.16) which would indicate higher intelligence with higher pTau burden. The non-significance rather points to a low statistical power due to the low sample size. Thus, the study confirms that pTau (as well as Aβ deposits) can be found in patients with drug-refractory temporal lobe epilepsy, but the association with global cognitive performance remains somewhat unclear.
All of the five presented studies analyzed pTau in surgical biopsy specimens of patients who had undergone epilepsy surgery for drug-refractory temporal lobe epilepsy. The prevalence of pTau ranged from 3.5-95%. The lowest prevalence was found in the largest study [3]. The findings regarding the relationship between pTau and neuropsychological performance were heterogeneous. All studies analyzed presurgical cognitive performance, but only 2/5 (40%) found an inverse association with pTau burden, one study with regard to executive functions [2] and the other with regard to language function (i.e. naming) and verbal short-term memory [4]. While naming is associated with the temporal lobe (via the ventral stream also known as the "what pathway") [6], executive functions and verbal short-term memory are rather depending on a extratemporal fronto-parietal network [7,8]. Thus, a relationship of the latter functions with pTau in temporal and/or hippocampal tissue is very unexpected. However, one potential explanation could be that there is a more widespread affection of the brain, but the chosen methodology is limited to demonstrate pTau only in the resected tissue of the temporal lobe (i.e. a sampling bias). Post-mortem studies as published by Thom and colleagues [9] could be one approach to demonstrate the pTau distribution in the brain. However, in vivo approaches to assess pTau in the whole brain would be appreciated such as positron emission tomography (PET) [10].
Solely one study [1] also analyzed longitudinal cognitive data and found inverse relationships between pTau and cognitive decline in verbal learning and long-term memory as well as in naming. However, the authors found no association with presurgical performance. The largest study by Silva et al. [3] did also not find a significant correlation between pTau and presurgical memory performance, but it must be considered that this study also found the lowest prevalence of pTau. Thus, no clear picture emerges regarding the relationship between pTau and cognition in temporal lobe epilepsy.
In this respect, the apparent heterogeneity across the studies regarding the demographic characteristics of the study cohorts (Table 1) as well as the neuropathological (Table 2) and the neuropsychological methods (Table 3) needs to be discussed. First of all, the sample sizes range from 12-56 patients with a total number of 142 patients. Three of the studies have a sample size lower than 30 patients. Regarding the analysis of the relationship between pTau and neuropsychological performance (Table 3), the sample sizes drop by up to 45% ranging from 8-52 patients (total: 96-117 patients). The average age of the patients varies from 34 to 54 years across studies and the total age range is 10-68 years. The age at epilepsy onset ranges from 0-66. Therefore, elderly patients with late new onset epilepsy (≥50 years) appear to be very rare. When looking at the neuropathological approaches, one study solely analyzed the hippocampal formation [4], whereas one study only focused on the temporal cortex [5]. The other three studies determined pTau in both locations; one of these three found pTau only in the temporal cortex [3], one mostly in the temporal cortex [1] and one in both the hippocampus and temporal cortex [2]. Individual studies encounter mixed pathologies, in which tauopathy may be intrinsically associated with primary lesions [11]. The neuropsychological methods are also very heterogeneous in terms of cognitive domains and employed test instruments. The studies assessed 1-6 cognitive domains assessed via a total of 1-9 tests. In the light of temporal lobe surgery, the most frequently addressed cognitive domain was (material-specific) episodic long-term memory (4/5 studies) followed by language (3/5 studies) and intelligence (3/5 studies). Each of the studies assessing material-specific long-term memory employed different tests, whereas all three used intelligence tests are derivates of the WAIS. The heterogeneity of neuropsychological tests is in line with national and international surveys on neuropsychological practice in epilepsy centers [12,13,14]. However, tests can differ in their validity to assess temporal and hippocampal dysfunction [15,16,17] and thus be more or less suited to demonstrate a potential relationship between pTau and memory performance.
Finally, it is important to underscore that the etiology of cognitive deficits in epilepsy is multifactorial [18,19,20]. Potential effects of the active epilepsy (epileptic seizures and interictal epileptic discharges) [21,22], the underlying pathology [23,24,25], the antiseizure medication [26,27], psychiatric comorbidities [28] need to be taken into consideration along with compensatory mechanisms (reserve capacities, plasticity) [29,30] and neurodevelopmental aspects (developmental hindrance, senescence) [31,32].
In a recent study [33], we performed an in-depth reanalysis of resective specimens from patients who had undergone epilepsy surgery and showed an unexpected cognitive decline in the time thereafter in addition to any direct surgical effects. First of all, with 30/355 patients (8%), unexpected cognitive deterioration was rare. Among the 24 patients with available specimens, 71% had further neuropathological changes in addition to the typical spectrum (such as hippocampal sclerosis, focal cortical dysplasias, etc.), including a secondary, putatively epilepsy-independent neurodegenerative disease process, limbic inflammation or "hippocampal gliosis" without segmental neurodegeneration. PTau was found in only 3 of the patients (12.5%) and solely in temporal specimens. It is important to note that cognitive decline is not typical in chronic epilepsy [32,34] and should always prompt a thorough investigation of the underlying cause [35,36].

Conclusions

The role of pTau in cognitive dysfunction and decline is currently a hot topic in the field of epilepsy since pTau may connect epilepsy and dementia. The available studies, however, which determined pTau burden in resected specimens from patients with drug-refractory temporal lobe epilepsy provide inconsistent findings. This may be due to heterogeneity across the studies with regard to the demographic characteristics of the patient cohorts as well as the neuropathological and the neuropsychological methods. Another challenge is the often complex etiology of cognitive impairments in people with epilepsy. Future studies would be appreciated that quantify pTau burden in vivo at the whole-brain level or in CSF and employ evidence-based cognitive measures to analyze potential relationships, taking other important cognition-related impact factors into consideration.

Disclosures

JAW reports personal fees from Eisai, outside the submitted work. CH reports honoria for speeches, webinars, counseling etc. from UCB, Eisai, Angelini, GW, Precisis, Jazz Pharma, honoraria for expert testimonies, as well as license fees from UCB and Eisai, outside the submitted work. The other authors have no potential conflicts of interest.

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