Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms

Tau pathology is repeatedly found in human epilepsy.

“Furthermore, tau pathology is repeatedly found in human epilepsy (Sanchez et al., 2018).”

• cites Sanchez et al., 2018 sourceSupported

Neurodegenerative conditions characterized by hyperphosphorylated tau aggregations exhibit increased rates of epilepsy.

“Given that neurodegenerative conditions characterized by hyperphosphorylated tau aggregations exhibit increased rates of epilepsy, epilepsies are being re-conceptualized within a tauopathy context (Xi et al., 2011; Sanchez et al., 2018; Ali et al., 2019).”

• cites Xi et al., 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sanchez et al., 2018 sourceSupported
• cites Ali et al., 2019 sourceSupported

Seizures are more common in Alzheimer's disease and dementia with Lewy bodies than in primary tauopathies, such as frontotemporal dementia and progressive supranuclear palsy.

“Seizures are more common in AD and dementia with Lewy bodies than in primary tauopathies, such as frontotemporal dementia and progressive supranuclear palsy (Beagle et al., 2017).”

• cites Beagle et al., 2017 sourcePartly supported

  The Results and Discussion report a higher cumulative incidence of seizures in AD and DLB than in FTD. The paper includes PSP among the FTD-spectrum disorders studied, but the passages do not establish a separate AD/DLB-versus-PSP comparison. They also do not characterize FTD as uniformly a primary tauopathy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Endogenous levels of tau positively correlate with chemically induced seizure susceptibility in wild-type mice.

“Endogenous levels of tau also positively correlate with chemically induced seizure susceptibility in wild-type mice (DeVos et al., 2013), suggesting a role of endogenous tau in mediating epileptic activity.”

• cites DeVos et al., 2013 sourceSupported

Seizures and hyperexcitability occur more frequently in primary tauopathies than in the general population.

“However, the possibility of seizures and hyperexcitability in primary tauopathies should not be ruled out, as they occur more frequently in these diseases than in the general population (Beagle et al., 2017; Sanchez et al., 2018).”

• cites Beagle et al., 2017 sourcePartly supported

  The Results report seizure incidence six times higher in the FTD cohort than in age-matched controls, and the Methods show that this cohort included PSP and corticobasal degeneration. But the paper does not establish an elevated seizure rate specifically for primary tauopathies: the Discussion instead identifies higher myoclonus propensity in those disorders. The claim extends the cohort-level seizure finding to a narrower disease group. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Sanchez et al., 2018 sourcePartly supported

  Section 3.2, “Seizures in PSP,” says PSP patients have seizures more frequently than the general population; Section 1 reports a higher seizure incidence in frontotemporal dementia. The paper discusses hyperexcitability in animal models but does not establish that hyperexcitability is more frequent across patients with primary tauopathies than in the general population. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In a post-mortem series of 138 refractory epilepsy cases, Braak staging of neurofibrillary tangles in the age group 40-65 years revealed increased Braak stages III/IV compared with age-matched non-epilepsy cases.

“In a post-mortem series of 138 refractory epilepsy cases of diverse causes, Braak staging of NFTs in the age group 40–65 years revealed increased Braak stages III/IV compared with data from an age-matched series of non-epilepsy cases (Thom et al., 2011).”

• cites Thom et al., 2011 sourceSupported

In the Scn1a model, postnatal injection of tau-targeting antisense oligonucleotides also reduces epileptic activity.

“This effect also occurs in the Scn1a model following postnatal injection of tau-targeting antisense oligonucleotides (Shao et al., 2022), suggesting that antisense oligonucleotides may be a promising treatment avenue for children with Dravet syndrome.”

• cites Shao et al., 2022 sourceSupported

Sustained increases in p-tau levels following kainic acid administration are accompanied by only transient increases in GSK-3β activity.

“However, the observation of sustained increases in p-tau levels following kainic acid administration being accompanied by only transient increases in GSK-3β activity (Liang et al., 2009) and the lack of effect on hippocampal p-tau by GSK-3β inhibitor pretreatment in the intra-amygdala kainic acid-induced status epilepticus mouse model (Alves et al., 2019) indicate that GSK-3β is not the only”

• cites Liang et al., 2009 sourceSupported

Genetic ablation of the CDK5 activator p35 increases susceptibility to spontaneous seizures in mice.

“For instance, genetic ablation of the CDK5 activator, p35, increases susceptibility to spontaneous seizures in mice (Chae et al., 1997).”

• cites Chae et al., 1997 sourceSupported

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.”

• cites Puvenna et al., 2016 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Smith et al., 2019 sourcePartly supported

  The Discussion (page not provided) reports tau deposition in 38% of a younger cohort with drug-resistant focal epilepsy, supporting the younger-patient portion of the claim. It does not establish a causal link between seizures and p-tau accumulation: the authors say further study is needed to determine whether tau contributes to epilepsy, follows seizure activity, or develops in parallel. This study did not examine the listed childhood-onset syndromes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Gourmaud et al., 2020 sourceSupported

Endogenous tau likely contributes to network hyperexcitability across primary and secondary epilepsies.

“Given tau’s role in modulating neuronal activity under normal physiological conditions (DeVos et al., 2013; Chang et al., 2021), endogenous tau likely contributes to network hyperexcitability across primary and secondary epilepsies.”

• cites DeVos et al., 2013 sourceSupported
• cites Chang et al., 2021 sourceSupported

Following kainic acid administration in mice, biphasic changes in p-tau levels occur, with decreased phosphorylation within the first 6-h period followed by a gradual 3-5-fold increase until a 48-h endpoint.

“Following kainic acid administration in mice, biphasic changes in p-tau levels occur, where decreased phosphorylation is first observed within the first 6-h period followed by a gradual 3–5-fold increase until a 48-h endpoint.”

• cites Liang et al., 2009 sourcePartly supported

  The Results section reports decreased tau phosphorylation within 6 hours of kainic acid injection, followed by increases reaching 3–4-fold at some sites and more than 5-fold at others. It does not support a gradual, uniform increase through 48 hours: phosphorylation rose quickly after 6 hours, remained elevated through 48 hours at one group of sites, and later declined at another. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Glycogen synthase kinase-3β is a relevant kinase responsible for tau phosphorylation.

“One relevant kinase responsible for tau phosphorylation is glycogen synthase kinase-3β (GSK-3β) (Toral-Rios et al., 2020).”

• cites Toral-Rios et al., 2020 sourceSupported

Analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, neurofibrillary tangles, and pre-tangles in 31 of 33 temporal lobe epilepsy patients between 50 and 65 years of age.

“For instance, analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, NFTs, and pre-tangles in 31 of 33 TLE patients between 50 and 65 years of age.”

• cites Tai et al., 2016 sourceSupported

Tau hyperphosphorylation is consistently present in the initial and long-term secondary mechanisms initiated by traumatic brain injury.

“Tau hyperphosphorylation is also consistently present in the initial and long-term secondary mechanisms initiated by traumatic brain injury (TBI) (Petraglia et al., 2014; Zheng et al., 2014; Rubenstein et al., 2015; Ali et al., 2019; Tan et al., 2020), a leading cause of morbidity and mortality worldwide (Hay et al., 2016).”

• cites Petraglia et al., 2014 sourcePartly supported

  The Results (Figure 4) report increased phosphorylated tau at 7 days and 1 month after both single and repetitive mild TBI, persisting at 6 months only after repetitive injury. The Discussion (Figure 6) says the increase after a single mild TBI clears by 6 months. Thus the paper supports early and long-term tau changes in its mouse model, but not their consistent long-term presence after TBI generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Zheng et al., 2014 sourcePartly supported

  The “PP2A Linkage to TBI” section reports increased phosphorylated tau from 10 minutes to 12 hours after injury in a compression-injury model. “Hyperphosphorylated Tau in TBI” links hyperphosphorylated tau to severe TBI and to chronic changes after repeated concussions. These passages support early and later associations, but not the stronger claim that tau hyperphosphorylation is consistently present throughout the initial and long-term secondary mechanisms of TBI. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Rubenstein et al., 2015 sourcePartly supported

  The Results report elevated phosphorylated tau in the acute phase after severe TBI and in most serum samples collected up to approximately six months later. However, the Discussion says its relationship to the acute injury cascade remains unclear. The paper supports an acute and longer-term association, not consistent presence throughout TBI’s secondary mechanisms. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Increased levels of p-tau in the brain are found across many seizure disorders.

“While levels of endogenous or total tau differ across examinations of patients with epilepsy, increased levels of p-tau in the brain are found across many seizure disorders (Thom et al., 2011).”

• cites Thom et al., 2011 sourcePartly supported

  The Discussion (page not provided) reports age-accelerated tau accumulation in a post-mortem series of patients with mainly long histories of drug-resistant epilepsy. That supports abnormal brain tau pathology in this group, but not increased p-tau levels across many seizure disorders. The Abstract (page not provided) also says traumatic brain injury, rather than seizures, was associated with tau accumulation in this series. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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).”

• cites Thom et al., 2011 sourceSupported
• cites Puvenna et al., 2016 sourceSupported
• cites Tai et al., 2016 sourceSupported

Tau pathology is not universally found in connection with epileptic activity.

“It should also be noted that tau pathology is not universally found in connection with epileptic activity.”

• cites Thom et al., 2011 sourceSupported
• cites Silva et al., 2021 sourceNot checked — no full text of the source

GSK-3β inhibition produces anticonvulsant effects against pentylenetetrazol-induced seizures in zebrafish larvae.

“and produces anticonvulsant effects against pentylenetetrazol-induced seizures in zebrafish larvae (Aourz et al., 2019).”

• cites Aourz et al., 2019 sourceSupported

A mechanism by which epileptogenesis gives rise to tau hyperphosphorylation may underlie the high incidence of tauopathy and epilepsy co-pathology found in diseases such as Alzheimer's disease and dementia with Lewy bodies.

“A mechanism by which epileptogenesis gives rise to tau hyperphosphorylation may underlie the high incidence of tauopathy and epilepsy co-pathology that is found in diseases such as AD and dementia with Lewy bodies (Vossel et al., 2016, 2017; Beagle et al., 2017).”

• cites Vossel et al., 2016, 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Beagle et al., 2017 sourcePartly supported

  The Introduction links epileptiform activity in AD to potentially increased tau production, and the Discussion reports seizures in AD and DLB alongside pathological tau. Neither section says that epileptogenesis causes tau hyperphosphorylation or establishes that mechanism as an explanation for the co-pathology. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Tau aggregation positively correlated with traumatic brain injury severity and the presence of seizure-like clonic shaking in a transgenic zebrafish model.

“Tau aggregation positively correlated with TBI severity and the presence of seizure-like clonic shaking.”

• cites Alyenbaawi et al., 2021 sourceSupported

Sustaining even a single traumatic brain injury can result in progressive neurofibrillary tangle formation that is more extensive and severe than what is expected with normal aging.

“For instance, sustaining even a single TBI can result in progressive NFT formation that is more extensive and severe than what is expected with normal aging (Johnson et al., 2012; Zanier et al., 2018).”

• cites Johnson et al., 2012 sourceSupported
• cites Zanier et al., 2018 sourcePartly supported

  The Results report more extensive neurofibrillary tangles and other tau pathology in survivors of a single moderate or severe TBI than in age-matched controls. Progressive spread was observed in mice after severe TBI, but the Discussion says the human data could not establish an association between time since injury and the extent of tau pathology. The claim therefore overextends the evidence for progressive tangle formation in humans and does not specify injury severity. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In animal models of temporal lobe epilepsy, tau hyperphosphorylation is observed in the amygdala, hippocampus, and cortex following chemical and electrical amygdala kindling.

“In animal models of TLE, tau hyperphosphorylation is observed in relevant brain regions, including the amygdala, hippocampus, and cortex, following chemical and electrical amygdala kindling (Jones et al., 2012; Liu et al., 2016; Alves et al., 2019).”

• cites Jones et al., 2012 sourceNot checked — no full text of the source
• cites Liu et al., 2016 sourceNot checked — no full text of the source
• cites Alves et al., 2019 sourcePartly supported

  The Results (page not available) report increased tau phosphorylation in the hippocampus after chemically induced status epilepticus from an intra-amygdala kainic acid injection. The cited paper does not establish tau hyperphosphorylation in the amygdala or cortex, or after electrical amygdala kindling; its mention of cortical injury is not a phosphorylation finding. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

GSK-3β inhibitor pretreatment lacks effect on hippocampal p-tau in the intra-amygdala kainic acid-induced status epilepticus mouse model.

“and the lack of effect on hippocampal p-tau by GSK-3β inhibitor pretreatment in the intra-amygdala kainic acid-induced status epilepticus mouse model (Alves et al., 2019) indicate that GSK-3β is not the only kinase responsible for tau phosphorylation following epileptic activity.”

• cites Alves et al., 2019 sourceSupported

Progressive activation of CDK5 co-occurs with increasing tau phosphorylation in rodent seizure models.

“Furthermore, progressive activation of CDK5 co-occurs with increasing tau phosphorylation in rodent seizure models (Chen et al., 2000; Liang et al., 2009), indicating significant mediation of seizure-associated tau hyperphosphorylation by CDK5.”

• cites Chen et al., 2000 sourcePartly supported

  The Results section (‘Evidence of increased cdk5 catalytic activity after chronic ECS treatment’; page not available) reports increased phosphorylated tau and the CDK5 activator p25 in rat hippocampus after chronic seizures. The Discussion says these findings are consistent with increased CDK5 catalytic activity, but the paper does not show a progressive rise in either measure over time or directly measure CDK5 catalytic activity. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Liang et al., 2009 sourceSupported

Animal models reveal increased p-tau levels in the brain associated with traumatic brain injury-induced epileptic activity.

“and animal models reveal increased p-tau levels in the brain associated with TBI-induced epileptic activity (Cho et al., 2020; Alyenbaawi et al., 2021).”

• cites Cho et al., 2020 sourceNot checked — no full text of the source
• cites Alyenbaawi et al., 2021 sourcePartly supported

  The Results (‘Post-traumatic seizure intensity influences tauopathy progression’; page unavailable) report more tau aggregates in TBI-treated zebrafish larvae that displayed seizure-like behavior, supporting the association. But this paper measures Tau aggregates, not increased phosphorylated tau (p-tau) levels; its Discussion mentions p-tau expression only when describing a separate epilepsy study. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

31% of the post-mortem refractory epilepsy cases studied by Thom et al. (2011) were classified as Braak Stage 0.

“For instance, 31% of the post-mortem refractory epilepsy cases studied by Thom et al. (2011) were classified as Braak Stage 0, and analysis of surgically resected tissue from 56 TLE patients by Silva et al. (2021) found p-tau-positive neurons in only two samples.”

• cites Thom et al., 2011 sourceSupported

Both GSK-3β and CDK5 play a role in neuronal excitability through involvement in GABAergic and glutamatergic neurotransmission.

“Both GSK-3β and CDK5 play a role in neuronal excitability through involvement in GABAergic and glutamatergic neurotransmission, and inhibiting their activity can affect network activity through various mechanisms (Sen et al., 2008; Jaworski, 2020; Toral-Rios et al., 2020; Banerjee et al., 2021).”

• cites Sen et al., 2008 sourceNot checked — no full text of the source
• cites Jaworski, 2020 sourceSupported
• cites Toral-Rios et al., 2020 sourcePartly supported

  The “GSK3β and Epilepsy” section links GSK3β to hyperexcitability through NMDA and glutamate AMPA receptors, and reports anticonvulsant activity from GSK3β inhibition (page not provided). The “Therapeutics” section mentions CDK5 as a tau kinase, but our copy does not link CDK5 to neuronal excitability or either kinase to GABAergic neurotransmission. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In humans, tau mRNA expression and protein levels in the brain can vary greatly.

“In humans, tau mRNA expression and protein levels in the brain can vary greatly (Trabzuni et al., 2012).”

• cites Trabzuni et al., 2012 sourceSupported

It is possible that epileptic activity in primary tauopathies is clinically underrecognized due to being non-motor or subclinical in nature, as suggested by the detection of subclinical epileptic activity in over 40% of Alzheimer's disease patients during overnight electroencephalography and 1-h magnetoencephalogram recordings.

“However, it is also possible that epileptic activity in these tauopathies is clinically underrecognized due to being non-motor or subclinical in nature, as suggested by the detection of subclinical epileptic activity in over 40% of AD patients during overnight electroencephalography and 1-h magnetoencephalogram recordings (Vossel et al., 2016).”

• cites Vossel et al., 2016 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Selective genetic ablation of tau in hippocampal excitatory neurons but not in inhibitory neurons mediates the neuroprotective effects of tau reduction in the Scn1a model.

“Shao et al. (2022) further found that selective genetic ablation of tau in hippocampal excitatory neurons but not in inhibitory neurons mediates the neuroprotective effects of tau reduction in the Scn1a model.”

• cites Shao et al., 2022 sourcePartly supported

  The Results report that tau ablation in excitatory, but not inhibitory, neurons reduced epileptic activity, and the Discussion describes benefits in the Scn1a Dravet syndrome model. However, the Results specify excitatory neurons across multiple forebrain regions, including the hippocampus and neocortex; the study does not isolate hippocampal excitatory neurons as the mediating population. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Active GSK-3β also activates mTOR.

“Given that active GSK-3β also activates mTOR (Mueed et al., 2018), tau hyperphosphorylation resulting from seizure-associated GSK-3β upregulation may be further exacerbated by GSK-3β-mediated mTOR activation (Caccamo et al., 2013; Figure 2).”

• cites Mueed et al., 2018 sourceSupported

Laforin is a tau phosphatase.

“Laforin is another tau phosphatase (Puri et al., 2009), though further research is required to investigate connections between hyperexcitability states and laforin downregulation in other seizure disorders.”

• cites Puri et al., 2009 sourceSupported

In younger temporal lobe epilepsy patients, an association between post-operative naming decline and subtle tau hyperphosphorylation localized to only the subiculum and dentate gyrus suggests that tau-associated pathological changes in relevant brain regions over time may underlie progressive cognitive impairment seen in temporal lobe epilepsy.

“In younger TLE patients, an association between post-operative naming decline and subtle tau hyperphosphorylation localized to only the subiculum and dentate gyrus suggest that tau-associated pathological changes in relevant brain regions over time may underlie progressive cognitive impairment seen in TLE (Prada Jardim et al., 2018).”

• cites Prada Jardim et al., 2018 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of autism spectrum disorder and Dravet syndrome provide evidence for a role of tau in mediating cognitive impairment in these diseases.

“Furthermore, the neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of ASD and Dravet syndrome (Gheyara et al., 2014; Tai et al., 2020) provide evidence for a role of tau in mediating cognitive impairment in these diseases as well.”

• cites Gheyara et al., 2014 sourceSupported
• cites Tai et al., 2020 sourceSupported

Individuals with dementia have higher rates of epilepsy.

“While individuals with dementia have higher rates of epilepsy, seizures are experienced more frequently in tauopathy-associated dementias like AD than in other dementias (Sanchez et al., 2018).”

• cites Sanchez et al., 2018 sourceSupported

Cognitive decline is accelerated in patients who have both Alzheimer's disease and seizures compared to those with only Alzheimer's disease.

“Cognitive decline is also accelerated in patients who have both AD and seizures compared to those with only AD (Vossel et al., 2017), suggesting that pathological tau and seizures can synergistically worsen cognitive outcomes.”

• cites Vossel et al., 2017 sourcePartly supported

  The Risk of seizures in Alzheimer’s disease section reports that patients with advanced Alzheimer’s disease who developed seizures had faster declines in language scores over 12 months than severity-matched patients without seizures. The Conclusions section says patients with Alzheimer’s disease and seizures *can* show accelerated cognitive decline. The claim presents that qualified finding as a general outcome for patients with both conditions. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Activation of mTOR is a proposed driver of tau pathology given the involvement of tau-related kinases both upstream and downstream of mTOR signaling and the contribution of mTOR-mediated autophagy dysfunction to tau hyperphosphorylation.

“Activation of mTOR is also a proposed driver of tau pathology given the involvement of tau-related kinases both upstream and downstream of mTOR signaling (Figure 2) and the contribution of mTOR-mediated autophagy dysfunction to tau hyperphosphorylation (Tramutola et al., 2017; Mueed et al., 2018).”

• cites Tramutola et al., 2017 sourceNot checked — no full text of the source
• cites Mueed et al., 2018 sourceSupported

Tau hyperphosphorylation resulting from seizure-associated GSK-3β upregulation may be further exacerbated by GSK-3β-mediated mTOR activation.

“tau hyperphosphorylation resulting from seizure-associated GSK-3β upregulation may be further exacerbated by GSK-3β-mediated mTOR activation (Caccamo et al., 2013; Figure 2).”

• cites Caccamo et al., 2013 sourcePartly supported

  The Results (page unavailable) report that increasing mTOR signaling increases tau phosphorylation through a GSK-3β-mediated mechanism. They do not show that GSK-3β activates mTOR; the proposed direction of that link is reversed. The paper also does not establish seizure-associated GSK-3β upregulation, although the Discussion mentions epilepsy as a feature of tuberous sclerosis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Abnormal p-tau in the form of neurofibrillary tangles are observed in the Epm2a-/- mouse model.

“Similarly, abnormal p-tau in the form of NFTs are also observed in the Epm2a–/– mouse model (Puri et al., 2009), which replicates many of the features of Lafora disease caused by EPM2A mutations, including laforin deficiency, neuronal degeneration, spontaneous epileptic activity, and the development of Lafora bodies (Ganesh et al., 2002).”

• cites Puri et al., 2009 sourceSupported

Endogenous tau enables mTOR activation through a disinhibition mechanism whereby tau inhibits phosphatase and tensin homolog deleted chromosome 10, which normally inhibits mTOR.

“Endogenous tau enables mTOR activation through a disinhibition mechanism whereby tau inhibits phosphatase and tensin homolog deleted chromosome 10 (PTEN), which normally inhibits mTOR (Tai et al., 2020; Figure 3).”

• cites Tai et al., 2020 sourceSupported

Downstream targets of mTOR activation include signaling cascades involving 4EBP1, S6K1, and CDK5, all of which result in tau phosphorylation.

“For instance, the downstream targets of mTOR activation include signaling cascades involving 4EBP1, S6K1, and CDK5, all of which result in tau phosphorylation (Mueed et al., 2018).”

• cites Mueed et al., 2018 sourcePartly supported

  The figure caption and “Downstream Components of mTOR” section identify 4EBP1 and S6K1 as downstream of mTOR and link their cascades to tau hyperphosphorylation. The “mTOR and Tau” section identifies CDK5 as a kinase involved in tau phosphorylation, but the paper does not identify it as a downstream target of mTOR. No page numbers are available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Reduced autophagy resulting from mTOR overactivation is implicated in elevated endogenous tau levels in the TSC2 mouse model of tuberous sclerosis complex.

“Furthermore, reduced autophagy resulting from mTOR overactivation is implicated in elevated endogenous tau levels in the TSC2 mouse model of TSC (Caccamo et al., 2013).”

• cites Caccamo et al., 2013 sourceSupported

The biphasic p-tau progression after kainic acid is accompanied by a corresponding increase and then decrease in activation of protein phosphatase 2A.

“This progression is accompanied by a corresponding increase and then decrease in the activation of protein phosphatase 2A (PP2A) (Liang et al., 2009), which is estimated to account for 70% of human brain tau dephosphorylation (Wang and Mandelkow, 2016).”

• cites Liang et al., 2009 sourceSupported

In the Epm2a-/- model, pathological tau levels are associated with increased GSK-3β activation.

“At least in the Epm2a–/– model, pathological tau levels are also associated with increased GSK-3β activation (Puri et al., 2009), suggesting that tau hyperphosphorylation is not mediated by the absence of laforin alone in Lafora disease.”

• cites Puri et al., 2009 sourceSupported

mTOR hyperactivity could prevent clearance of both normal and pathological tau.

“Therefore, mTOR hyperactivity could prevent clearance of both normal and pathological tau (Chesser et al., 2013).”

• cites Chesser et al., 2013 sourceSupported

mTOR hyperactivation accompanies epileptic activity across animal models of temporal lobe epilepsy, post-traumatic epilepsy, focal cortical dysplasia II, Dravet syndrome, autism spectrum disorder, and tuberous sclerosis complex.

“Furthermore, mTOR hyperactivation accompanies epileptic activity across different seizure models including animal models of TLE, PTE, FCDII, Dravet syndrome, ASD, and TSC (Meikle et al., 2007; Zeng et al., 2008; Sha et al., 2012; Guo et al., 2013; Gheyara et al., 2014; Butler et al., 2015; Marsan and Baulac, 2018; Tai et al., 2020; Shao et al., 2022).”

• cites Meikle et al., 2007 sourceSupported
• cites Zeng et al., 2008 sourceNot checked — no full text of the source
• cites Sha et al., 2012 sourcePartly supported

  The Introduction reports mTOR overactivation in rodent models of temporal lobe epilepsy, and the Discussion describes activation in the paper’s TLE mouse model. The paper also discusses a mouse model of tuberous sclerosis complex, but the cited passages do not support the claim across post-traumatic epilepsy, focal cortical dysplasia II, Dravet syndrome, or autism spectrum disorder models. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Seizures are experienced more frequently in tauopathy-associated dementias like Alzheimer's disease than in other dementias.

“seizures are experienced more frequently in tauopathy-associated dementias like AD than in other dementias (Sanchez et al., 2018).”

• cites Sanchez et al., 2018 sourceSupported

Post-mortem analysis of 138 refractory epilepsy cases revealed that 77% of patients with Braak staging III or higher exhibited progressive cognitive decline.

“Post-mortem analysis of 138 refractory epilepsy cases revealed that 77% of patients with Braak staging III or higher exhibited progressive cognitive decline (Thom et al., 2011), and increased total and p-tau levels measured in surgically resected tissue from TLE patients are inversely correlated with cognitive scores (Kandratavicius et al., 2013; Tai et al., 2016; Gourmaud et al., 2020).”

• cites Thom et al., 2011 sourceSupported

Increased total and p-tau levels measured in surgically resected tissue from temporal lobe epilepsy patients are inversely correlated with cognitive scores.

“and increased total and p-tau levels measured in surgically resected tissue from TLE patients are inversely correlated with cognitive scores (Kandratavicius et al., 2013; Tai et al., 2016; Gourmaud et al., 2020).”

• cites Kandratavicius et al., 2013 sourcePartly supported

  Results §3.3 links greater tau immunoreactivity in CA2 of surgical MTLE specimens to below-average verbal scores, supporting the claim's direction for tau and cognition. Methods §2.3 specifies an antibody for total tau regardless of phosphorylation state; the paper does not report separate p-tau levels. The CA2 finding is a comparison between score groups, not a reported inverse correlation between tau levels and cognitive scores. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Tai et al., 2016 sourcePartly supported

  The Methods (Analysis of tau and amyloid pathology; page unavailable) describe a score of hyperphosphorylated-tau staining in resected temporal lobe tissue, not measurements of both total tau and p-tau levels. The Results (Modified tau score in relation to age and cognitive testing; page unavailable) report negative correlations with changes in verbal learning, recall, and naming scores over the year after surgery, but no significant correlation with preoperative scores. The claim is supported for p-tau burden and subsequent cognitive decline, not for total tau levels or cognitive scores generally. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Gourmaud et al., 2020 sourceSupported

Resulting tau hyperphosphorylation and aggregation may in turn further contribute to cognitive impairments seen in some seizure disorders.

“Resulting tau hyperphosphorylation and aggregation may in turn further contribute to cognitive impairments seen in some seizure disorders.”

Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models.

“Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models.”

Pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects.

“Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects.”

Endogenous tau helps enable network hyperexcitability.

“we propose a potential overarching mechanism (Figure 1) whereby endogenous tau helps enable network hyperexcitability, which triggers homeostatic responses aimed, in part, to disable tau activity by phosphorylation.”

Network hyperexcitability triggers homeostatic responses aimed, in part, to disable tau activity by phosphorylation.

“we propose a potential overarching mechanism (Figure 1) whereby endogenous tau helps enable network hyperexcitability, which triggers homeostatic responses aimed, in part, to disable tau activity by phosphorylation.”

Reducing or ablating tau attenuates network hyperexcitability in both Alzheimer's and epilepsy models.

“Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models.”

The deposition of hyperphosphorylated tau in the brain is associated with epilepsy and network hyperexcitability in a variety of neurological diseases.

“The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases.”

An increase in p-tau and tau aggregation promotes kindling-induced epileptogenesis.

“These findings suggest that an increase in p-tau and tau aggregation promotes kindling-induced epileptogenesis.”

In classical tauopathies where overt epilepsy infrequently occurs, tau hyperphosphorylation can arise from a variety of different causes.

“In classical tauopathies where overt epilepsy infrequently occurs, tau hyperphosphorylation can arise from a variety of different causes (Kovacs, 2017).”

• cites Kovacs, 2017 sourceNot checked — no full text of the source

CDK5 inhibition by roscovitine and olomoucine prevents cytoskeletal protein phosphorylation.

“and CDK5 inhibition by roscovitine and olomoucine prevents cytoskeletal protein phosphorylation (Bu et al., 2002; Zhang et al., 2004, 2008).”

• cites Bu et al., 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhang et al., 2004, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Analysis of surgically resected tissue from 56 temporal lobe epilepsy patients by Silva et al. (2021) found p-tau-positive neurons in only two samples.

“and analysis of surgically resected tissue from 56 TLE patients by Silva et al. (2021) found p-tau-positive neurons in only two samples.”

• cites Silva et al., 2021 sourceNot checked — no full text of the source

Dysplastic cortical neurons in focal cortical dysplasia patients express CDK5 aggregations.

“and dysplastic cortical neurons in FCD patients express CDK5 aggregations (Sisodiya et al., 2002).”

• cites Sisodiya et al., 2002 sourceNot checked — no full text of the source

In the electrical amygdala kindling rodent model of temporal lobe epilepsy, tau-knockout mice do not differ from wild-type mice in seizure outcome following repeated kindling.

“Temporal lobe epilepsy (TLE) is one of the most prevalent forms of focal epilepsy (Tellez-Zenteno and Hernandez-Ronquillo, 2012; Asadi-Pooya et al., 2017), and in the electrical amygdala kindling rodent model of TLE, tau-knockout mice do not differ from wild-type mice in seizure outcome following repeated kindling (Liu S. et al., 2017).”

• cites Liu S. et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Tau hyperphosphorylation associated with seizure activity may also be due to a lack of tau dephosphorylation by tau phosphatases.

“In addition to kinase activity, tau hyperphosphorylation associated with seizure activity may also be due to a lack of tau dephosphorylation by tau phosphatases.”

Findings across different seizure disease models reveal a significant function of endogenous tau, as well as pathological tau, in the mediation of epileptic activity.

“Taken together, findings across different seizure disease models reveal a significant function of endogenous tau, as well as pathological tau, in the mediation of epileptic activity.”

GSK-3β is not the only kinase responsible for tau phosphorylation following epileptic activity.

“indicate that GSK-3β is not the only kinase responsible for tau phosphorylation following epileptic activity.”

Elevated tau measurements in cerebrospinal fluid correlate with seizure type and duration in patients with epilepsy.

“Elevated tau measurements in cerebrospinal fluid have in fact been shown to correlate with seizure type and duration in patients with epilepsy (Tumani et al., 2015).”

• cites Tumani et al., 2015 sourceNot checked — no full text of the source

Cyclin-dependent kinase 5 is another protein kinase highly implicated in tau phosphorylation.

“Another protein kinase highly implicated in tau phosphorylation is cyclin-dependent kinase 5 (CDK5).”

• cites Cruz et al., 2003 sourceNot checked — no full text of the source

CDK5 overactivation is present in resected tissue from refractory epilepsy patients.

“As is seen with GSK-3β, CDK5 overactivation is present in resected tissue from refractory epilepsy patients (Xi et al., 2009; Liu X. et al., 2017), and dysplastic cortical neurons in FCD patients express CDK5 aggregations (Sisodiya et al., 2002).”

• cites Xi et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Liu X. et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Upregulation of GSK-3β is found in surgically resected tissue samples from patients with intractable epilepsy.

“Upregulation of GSK-3β is found in surgically resected tissue samples from patients with intractable epilepsy (Xi et al., 2009; Liu X. et al., 2017), and GSK-3β overactivation co-occurs with increased p-tau levels in mesial TLE patients (Liu C. et al., 2017).”

• cites Xi et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Liu X. et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

High levels of endogenous tau may predict a person's susceptibility to epileptic activity.

“And though exact reasons for individual differences in endogenous tau levels remain unknown, high levels may consequently predict a person’s susceptibility to epileptic activity.”

GSK-3β overactivation co-occurs with increased p-tau levels in mesial temporal lobe epilepsy patients.

“and GSK-3β overactivation co-occurs with increased p-tau levels in mesial TLE patients (Liu C. et al., 2017).”

• cites Liu C. et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In the genetic mouse model of Niemann-Pick type C disease, increased activation of CDK5 and its activator p25 coincides spatially and temporally with tau pathology.

“For example, in the genetic mouse model of NPC, increased activation of CDK5 and its activator, p25, coincides spatially and temporally with tau pathology, and CDK5 inhibition by roscovitine and olomoucine prevents cytoskeletal protein phosphorylation (Bu et al., 2002; Zhang et al., 2004, 2008).”

• cites Bu et al., 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhang et al., 2004, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The absence of pathological tau deposition in some epilepsy cases indicates that epileptogenesis does not always lead to tauopathies.

“The absence of pathological tau deposition in these cases indicates that epileptogenesis does not always lead to tauopathies.”

Sodium selenate is a specific agonist for PP2A expressing the regulatory B subunit, an essential subunit for tau dephosphorylation by PP2A.

“Sodium selenate is a specific agonist for PP2A expressing the regulatory B subunit, an essential subunit for tau dephosphorylation by PP2A (Jones et al., 2012; Liu et al., 2016), and shows promise as a potential antiepileptic treatment option.”

• cites Jones et al., 2012 sourceNot checked — no full text of the source
• cites Liu et al., 2016 sourceNot checked — no full text of the source

Long-lasting phosphatase downregulation occurs, as evidenced by decreased PP2A activity paired with increased p-tau levels in epileptogenic brain regions following post-kainic acid status epilepticus, amygdala kindling, and fluid percussion injury in rats.

“However, long-lasting phosphatase downregulation ultimately occurs, as evidenced by decreased PP2A activity paired with increased p-tau levels observed in epileptogenic brain regions following post-kainic acid status epilepticus, amygdala kindling, and fluid percussion injury in rats (Liu et al., 2016).”

• cites Liu et al., 2016 sourceNot checked — no full text of the source

Tuberous sclerosis complex is associated with increased p-tau.

“| Tuberous sclerosis complex | All ages | Tumors, seizures, cognitive disability | ↑ p-tau | mTOR, GSK-3β | Rapamycin, lithium |”

Nodding syndrome is associated with pre-tangles and neurofibrillary tangles.

“| Nodding syndrome | Childhood, adolescence | Seizures (vertical head nodding), cognitive and motor disability | Pre-tangles, NFTs | Unknown | |”

GSK-3β upregulation causes PP2A activation.

“For instance, GSK-3β upregulation causes PP2A activation (Wang et al., 2015).”

• cites Wang et al., 2015 sourceNot checked — no full text of the source

Lack of phosphatase activity may also contribute to epileptic activity.

“Interestingly, the lack of phosphatase activity may also contribute to epileptic activity.”

Tau hyperphosphorylation is prevalent across different types of epilepsies.

“the overlapping of tau-related cell signaling pathways and prevalence of tau hyperphosphorylation found throughout different types of epilepsies (Table 1)”

Tau hyperphosphorylation is not mediated by the absence of laforin alone in Lafora disease.

“suggesting that tau hyperphosphorylation is not mediated by the absence of laforin alone in Lafora disease.”

mTOR likely contributes to tau and seizure co-pathology.

“mTOR therefore likely contributes to tau and seizure co-pathology, warranting further pharmaceutical consideration of mTOR inhibition by rapamycin.”

Niemann-Pick disease is associated with increased p-tau and neurofibrillary tangles.

“| Niemann pick disease | All ages | Seizure, progressive neurodegeneration, cognitive decline | ↑ p-tau, NFTs | Cholesterol, mTOR, CDK5 | Rapamycin, CDK5 inhibitor |”

Epileptic activity can trigger homeostatic responses whereby enzymatic pathways disable endogenous tau by increased phosphorylation to stabilize aberrant network hyperexcitability.

“Given findings of upregulated kinase and downregulated phosphatase activity across different seizure disorders, we propose that epileptic activity can trigger homeostatic responses whereby enzymatic pathways disable endogenous tau by increased phosphorylation to stabilize aberrant network hyperexcitability.”

The combined effects of kinase upregulation and phosphatase downregulation contribute to progressive tau hyperphosphorylation and accumulation in seizure disorders.

“and that the combined effects of kinase upregulation and phosphatase downregulation contribute to progressive tau hyperphosphorylation and accumulation in seizure disorders.”

The antiepileptic effects of sodium selenate persist following drug washout in animal traumatic brain injury models.

“The antiepileptic effects of sodium selenate persist following drug washout in animal TBI models (Liu et al., 2016), highlighting a potential disease-modifying effect of PP2A upregulation by sodium selenate during epileptogenesis when applied in early PTE disease stage.”

• cites Liu et al., 2016 sourceNot checked — no full text of the source

It is possible that phosphatase activity is initially triggered to offset elevated tau phosphorylation caused by upregulated kinase activity following an epileptic event.

“It is possible that phosphatase activity is initially triggered to offset elevated tau phosphorylation caused by upregulated kinase activity following an epileptic event.”

Post-traumatic epilepsy is associated with mTOR and PP2A signaling pathways.

“| Post-traumatic epilepsy | Dependent on age of trauma | Seizures, cognitive decline | Acute: ↑ total tau, ↑ p-tau Chronic: ↑ p-tau, NFTs | mTOR, PP2A | Rapamycin, sodium selenate, tau reduction |”

Tau-related cell signaling pathways overlap across different types of epilepsies.

“the overlapping of tau-related cell signaling pathways and prevalence of tau hyperphosphorylation found throughout different types of epilepsies (Table 1)”

Cognitive impairment is a common comorbidity of seizure disorders.

“Cognitive impairment is a common comorbidity of seizure disorders.”

PP2A is estimated to account for 70% of human brain tau dephosphorylation.

“which is estimated to account for 70% of human brain tau dephosphorylation (Wang and Mandelkow, 2016).”

• cites Wang and Mandelkow, 2016 sourceNot checked — no full text of the source

Temporal lobe epilepsy is associated with mTOR, GSK-3β, and PP2A signaling pathways.

“| Temporal lobe epilepsy | All ages | Focal seizures, cognitive decline, hippocampal sclerosis | ↑ total tau, ↑ p-tau, neuropil threads, pre-tangles, NFTs | mTOR, GSK-3β, PP2A | Rapamycin, lithium, sodium selenate |”

Niemann-Pick disease is associated with cholesterol, mTOR, and CDK5 signaling pathways.

“| Niemann pick disease | All ages | Seizure, progressive neurodegeneration, cognitive decline | ↑ p-tau, NFTs | Cholesterol, mTOR, CDK5 | Rapamycin, CDK5 inhibitor |”

Autism spectrum disorder is associated with PTEN, PI3K, mTOR, and CDK5 signaling pathways.

“| Autism Spectrum disorder | Infancy to early childhood | Learning disability, anxiety and/or depression, seizures | ↑ total tau, ↑ p-tau | PTEN, PI3K, mTOR, CDK5 | Rapamycin, CDK5 inhibitor, tau reduction |”

Subsequent hyperphosphorylation and accumulation of tau results from overactivation of such mechanisms, especially with recurring epileptic activity and continuous epileptic states.

“Subsequent hyperphosphorylation and accumulation of tau results from overactivation of such mechanisms, especially with recurring epileptic activity, and continuous epileptic states.”

Tuberous sclerosis complex is associated with mTOR and GSK-3β signaling pathways.

“| Tuberous sclerosis complex | All ages | Tumors, seizures, cognitive disability | ↑ p-tau | mTOR, GSK-3β | Rapamycin, lithium |”

Seizures give rise to disruptions in the intricate balance of tau kinase and phosphatase activity.

“Taken together, the discussed findings indicate that seizures give rise to disruptions in the intricate balance of tau kinase and phosphatase activity and that the combined effects of kinase upregulation and phosphatase downregulation contribute to progressive tau hyperphosphorylation and accumulation in seizure disorders.”

Pathological tau and seizures can synergistically worsen cognitive outcomes.

“suggesting that pathological tau and seizures can synergistically worsen cognitive outcomes.”

Reducing tau may be beneficial in autism spectrum disorder and Dravet syndrome via PTEN disinhibition.

“suggesting that reducing tau may be beneficial in these diseases via PTEN disinhibition.”

Focal cortical dysplasia IIb is associated with increased p-tau and neurofibrillary tangles.

“| Focal cortical dysplasia IIb | Infancy to early adulthood | Refractory epilepsy | ↑ p-tau, NFTs | NMDA receptor NR2A/B subunit | CDK5 inhibitor |”

Lafora disease is associated with increased p-tau and neurofibrillary tangles.

“| Lafora disease | Adolescence | Seizures, dementia | ↑ p-tau, NFTs | Laforin, GLT-1 transporter, loss of GABAergic function | |”

mTOR functions as a negative regulator of autophagy.

“mTOR also functions as a negative regulator of autophagy (Tramutola et al., 2017).”

• cites Tramutola et al., 2017 sourceNot checked — no full text of the source

Tau hyperphosphorylation potentially contributes to progressive cognitive decline in seizure disorders.

“Furthermore, growing evidence indicates a potential contribution of tau hyperphosphorylation to progressive cognitive decline in seizure disorders.”

Endogenous tau has a significant mediating role in epileptogenesis.

“The antiseizure effect of tau ablation that can be reproduced in a variety of seizure models indicates a significant mediating role of endogenous tau in epileptogenesis.”

Dravet syndrome is associated with neurofibrillary tangles.

“| Dravet syndrome | Infancy | Refractory epilepsy, cognitive impairment | NFTs | NMDA receptor GluN2A subunit | GNE-0273, tau reduction |”