CoChat
Sign Up
Cited by 16Tuberous Sclerosis Complex ResearchAlzheimer's disease research and treatmentsEpilepsy research and treatment

Tuberous sclerosis complex is associated with a novel human tauopathy

Open access
Hwang, Ji-Hye L., Perloff, Olga S., Gaus, Stephanie E., Benitez, Camila, Alquezar, Carolina, Cosme, Celica Q., Nana, Alissa L., Vatsavayai, Sarat C. +5 more·2023·Acta Neuropathologica
DOI 10.1007/s00401-022-02521-5PMC PMC10244026
Open this paper in CoChat — free accountOpen PDF

Abstract

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30-58 years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant "TSC tauopathy" not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.

AI snapshot

Written from the paper’s full text.

TL;DR

In a post-mortem screen of adults with tuberous sclerosis complex (TSC), the authors identified a novel neurofibrillary tangle-predominant tauopathy in 3 of 11 TSC subjects, which they term “TSC tauopathy.” This tauopathy was absent in epilepsy and non-neurological controls and showed distinctive tau acetylation, 3R > 4R isoform predominance, and absent MC1/p62 staining.

Key findings

  • Among 11 adults with TSC aged 30–58 years, 3 (TS 6, 7, and 10) showed a neurofibrillary tangle-predominant “TSC tauopathy” not seen in age-matched epilepsy unrelated to TSC (n = 9) or non-neurological controls (n = 10).
  • TSC tauopathy occurred without pathological amyloid beta, TDP-43, or alpha-synuclein deposition; tau acetylation (K274, K343) was prominent in both TSC1 and TSC2 mutation carriers, whereas tau phosphorylation at S202 was observed only in TSC2 carriers.
  • The most consistent NFT burden involved inferior frontal gyrus, temporal pole, superior frontal gyrus, amygdala, and ventral striatum; NFTs showed 3-repeat > 4-repeat tau isoform pattern in both TSC1 and TSC2 carriers, with no MC1 or p62 immunolabeling.
  • Genetic screening identified 9 TSC2 carriers and one TSC1 mutation carrier; one subject had unknown genetic status due to lack of frozen tissue.

Methods

  • Post-mortem brain tissue was obtained from the NIH NeuroBioBank: TSC (n = 11), epilepsy unrelated to TSC (n = 9), and non-neurological controls (n = 10), matched as closely as possible for age and sex. Initial screening used phospho-tau (CP13, S202) and acetyl-tau (MAB359, K274) immunohistochemistry in anterior cingulate cortex, inferior frontal gyrus, and entorhinal/hippocampal complex.
  • Three TSC subjects with prominent tauopathy underwent regional mapping across 22 formalin-fixed blocks representing 43 cortical, subcortical, limbic, and brainstem areas; the remaining eight TSC subjects were re-screened in superior frontal gyrus, ventral striatum, amygdala, and temporal pole. TSC1/TSC2 genetic screening and Western blotting of heat-stable tau fractions were also performed.
  • NFT density was semi-quantitatively rated as absent, 1–5, 5–15, or more than 15 tangles per region-of-interest; scores were converted to integers (0–3) and averaged across subjects for heat map mapping.

Limitations

  • The paper states that detailed clinical information was lacking regarding seizure etiology, localization, and frequency in both groups, and that clinical information about TSC subjects was limited; quantitative seizure frequency was not available.
  • The authors state that additional neuropathological studies in TSC1 carriers are needed, that the TSC1 finding rests on a single carrier, and that expanding the adult TSC cohort is a next step.
  • Evident from the text: the TSC tauopathy finding is based on only 3 of 11 TSC subjects, characterization was limited by section availability, and the study cannot establish causality or prevalence in TSC.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00401-022-02521-5

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 31 cited sources checked · 11 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    Medial temporal and brainstem neurofibrillary changes were observed in older TSC subjects at a rate comparable to the epilepsy and non-neurological control groups and age-based norms.

    “Medial temporal and brainstem neurofibrillary changes were observed in our older TSC subjects, as expected, but at a rate comparable to that observed in the epilepsy and non-neurological control groups and age-based norms [3].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. https://doi.org/10.1097/NEN.0b013e318232a379 source
  • Premisecitation

    Frontal lobe tissue surgically resected from the patient's sibling showed elevated tau phosphorylation without evidence of tau aggregation or tangle formation.

    “Frontal lobe tissue surgically resected for treatment of TSC-related epilepsy from the patient’s living sibling showed elevated tau phosphorylation without evidence of tau aggregation or tangle formation [16].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0 source
  • Interpretationown data

    TSC tauopathy differs from other TSC-related tau abnormalities previously reported.

    “TSC tauopathy also differs from other TSC-related tau abnormalities previously reported in the TSC literature by our group [12, 16] and others [6, 11].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [12] Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA et al (2020) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol 77:358–366. https://doi.org/10.1001/jamaneurol.2019.4284 source
    • cites [16] Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0 source
    • cites [6] de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC et al (2015) Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 52:25–35. https://doi.org/10.1016/j.pediatrneurol.2014.10.004 source

      The Introduction discusses TSC, mTOR signaling, and neuropsychiatric difficulties, but does not discuss tauopathy or compare TSC-related tau abnormalities. Searches for tauopathy, tau abnormalities, tau protein, and neurofibrillary tangles found no passage addressing the claimed distinction. No page numbers were available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [11] Liu AJ, Lusk JB, Ervin J, Burke J, O’Brien R, Wang SJ (2022) Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation. Acta Neuropathol Commun 10:27. https://doi.org/10.1186/s40478-022-01330-x source
  • Findingown data

    In TS 7 and 10, both TSC2 mutation carriers, p-tau and especially ac-tau staining revealed an NFT-predominant tauopathy.

    “In TS 7 and 10, both TSC2 mutation carriers, p-tau and, especially, ac-tau staining revealed an NFT-predominant tauopathy (Figure 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    The TSC tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition.

    “This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 18

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior reports depict tau-related changes as elevated p-tau staining in the absence of frank neurofibrillary tangles.

    “Generally, prior reports depict tau-related changes as elevated p-tau staining in the absence of frank neurofibrillary tangles.”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [12] Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA et al (2020) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol 77:358–366. https://doi.org/10.1001/jamaneurol.2019.4284 source

      The Results (Cerebrospinal Fluid Biomarkers; page unavailable) report elevated phosphorylated tau in CSF, not elevated p-tau staining in tissue. The Results (Investigational Tau-PET Imaging Biomarker; page unavailable) mention neurofibrillary tangles as a target of the PET tracer in Alzheimer disease, but do not say that prior reports found staining without tangles. Searches for phosphorylated-tau staining, immunoreactivity, and neurofibrillary tangles found no passage establishing the claimed pattern. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [16] Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0 source

      In the paper’s neuropathology account (page unavailable), the affected sibling’s tissue showed phosphorylated-tau staining, and no neurofibrillary tangles were observed. This supports the described pattern in this case, but the case report does not establish that prior reports generally show the same pattern. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [6] de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC et al (2015) Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 52:25–35. https://doi.org/10.1016/j.pediatrneurol.2014.10.004 source

      The Introduction discusses mTOR signaling and neuropsychiatric difficulties in tuberous sclerosis, not tau pathology. Searches for p-tau staining and neurofibrillary tangles found no passage in our copy addressing either finding; page numbers were unavailable. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [11] Liu AJ, Lusk JB, Ervin J, Burke J, O’Brien R, Wang SJ (2022) Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation. Acta Neuropathol Commun 10:27. https://doi.org/10.1186/s40478-022-01330-x source

      The Introduction says prior studies found phosphorylated tau accumulation in TSC, but it does not say they found an absence of tangles. Contrary to the claimed depiction, the Results (Qualitative immunohistochemistry findings; page unavailable) explicitly report neurofibrillary tangles in patients with TSC. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The mTORC1 pathway controls translation, autophagy, and cell growth.

    “which controls a host of cellular processes, including translation, autophagy, and cell growth [8].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Feliciano DM (2020) The neurodevelopmental pathogenesis of tuberous sclerosis complex (TSC). Front Neuroanat 14:39. https://doi.org/10.3389/fnana.2020.00039 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Screening revealed low rates of Braak 1-2 NFT stages in all three groups, consistent with literature-based norms.

    “screening revealed low rates of Braak 1–2 NFT stages in all three groups (Table 2), consistent with literature-based norms [3].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. https://doi.org/10.1097/NEN.0b013e318232a379 source

      The section on neurofibrillary stages reports 589 Stage I and 497 Stage II cases among 2,332, providing literature-based frequencies for comparison. It does not establish that rates in the citing study’s three groups were low or consistent with those frequencies; those groups are not examined in this paper. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TSC1 haploinsufficiency induced tau acetylation at K343 and 6 other sites without affecting tau phosphorylation.

    “In recent model-based studies, TSC1 haploinsufficiency induced tau acetylation (at K343 and 6 other sites) without affecting tau phosphorylation [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Alquezar C, Schoch KM, Geier EG, Ramos EM, Scrivo A, Li KH et al (2021) TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy. Sci Adv 7:eabg3897. https://doi.org/10.1126/sciadv.abg3897 source

      The Results section (‘Tau from TSC1+/− cells undergoes aberrant acetylation that affects its degradation’; page not provided) reports no increase in tau phosphorylation and identifies six uniquely acetylated sites in TSC1+/− cells, including K343—not K343 plus six others. A seventh site, K174, was acetylated in both control and TSC1+/− cells. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The TSC1/TSC2 protein complex inhibits the mTORC1 pathway.

    “that inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Feliciano DM (2020) The neurodevelopmental pathogenesis of tuberous sclerosis complex (TSC). Front Neuroanat 14:39. https://doi.org/10.3389/fnana.2020.00039 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The TSC1 and TSC2 proteins form a poly-protein complex.

    “These proteins form a poly-protein complex [17, 25]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [17] Palmio J, Suhonen J, Keranen T, Hulkkonen J, Peltola J, Pirttila (2009) Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure. Seizure 18:474–477. https://doi.org/10.1016/j.seizure.2009.04.006 source

      The Introduction discusses tau protein’s role in microtubules, and the Methods describe measuring tau in cerebrospinal fluid after seizures. Searches for TSC1, TSC2, hamartin, tuberin, and a protein complex found no passage in our copy addressing whether TSC1 and TSC2 form a complex. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [25] Weaver CL, Espinoza M, Kress Y, Davies P (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21:719–727. https://doi.org/10.1016/s0197-4580(00)00157-3 source

  • May combine two claims.

    Interpretationown data

    The compact NFTs observed are morphologically most like those seen in primary age-related tauopathy (PART), Alzheimer's disease (AD), and chronic traumatic encephalopathy (CTE), but the topographical distribution and immunostaining characteristics differ from these more common tauopathies.

    “The compact NFTs observed are morphologically most like those seen in primary age-related tauopathy (PART) [4], Alzheimer’s disease (AD) [22], and chronic traumatic encephalopathy (CTE) [13, 14], but the topographical distribution and immunostaining characteristics differ from these more common tauopathies in several respects.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [4] Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. https://doi.org/10.1007/s00401-014-1349-0 source
    • cites [22] Sarnat HB, Flores-Sarnat L (2015) Infantile tauopathies: hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev 37:553–562. https://doi.org/10.1016/j.braindev.2014.08.010 source
    • cites [13] McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86. https://doi.org/10.1007/s00401-015-1515-z source

      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
    • cites [14] McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. https://doi.org/10.1093/brain/aws307 source

      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

  • May combine two claims.

    Premisecitation

    Adults with TSC showed mildly elevated CSF phosphorylated tau (pTau-181) levels and focal uptake on 18F-flortaucipir PET imaging, often near radiographically identified tubers.

    “Adults with TSC further showed mildly elevated CSF phosphorylated tau (pTau-181) levels and focal uptake on 18F-flortaucipir positron emission tomographic (FTP-PET) imaging, often in the vicinity of radiographically identified tubers.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA et al (2020) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol 77:358–366. https://doi.org/10.1001/jamaneurol.2019.4284 source

      The Results sections report elevated CSF P-tau in the TSC cohort and small foci of flortaucipir uptake in all three patients who underwent tau-PET. In two of those three, uptake corresponded to structural changes on brain MRI, but the paper does not specifically identify those changes as tubers; that detail is more specific than the reported finding. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A TSC1 mutation carrier presented with a progressive neurodegenerative syndrome that met clinical research criteria for behavioral variant frontotemporal dementia and showed prominent right anterior temporal lobe atrophy.

    “Recently, we reported a TSC1 mutation carrier who presented with a progressive neurodegenerative syndrome that met clinical research criteria for behavioral variant frontotemporal dementia (bvFTD) and showed prominent right anterior temporal lobe atrophy [16].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0 source

  • May combine two claims.

    Premisecitation

    PART, AD, and CTE all show a balanced 3R/4R tauopathy, prominent neuropil threads, and ready detection with CP13, MC1, and p62 antibodies.

    “Finally, PART, AD, and CTE all show a balanced 3R/4R tauopathy, prominent neuropil threads, and ready detection with CP13, MC1, and p62 antibodies [14, 20, 24]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [14] McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. https://doi.org/10.1093/brain/aws307 source

      The Neuropathology of chronic traumatic encephalopathy section reports that CTE tangles stain for both 3R and 4R tau, and Figure 1 describes CP-13-positive neuropil threads in CTE. It does not establish a balanced 3R/4R ratio or detection with MC1 and p62; the paper also does not address PART. Its comparison table discusses 3R and 4R tau in AD, but does not establish the full set of shared features claimed for all three conditions. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [20] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30 source

      The passages from the copy address sequence-variant classification, including pathogenicity criteria (Table 3, p. 34), not tau pathology. Searches for PART, AD, CTE, 3R/4R tau, neuropil threads, and the named antibodies found no passage addressing the claim. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [24] van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808. https://doi.org/10.1126/science.277.5327.805 source

  • Classified as probably not a substantial claim.

    Premisecitation

    TSC1 haploinsufficiency led to specific tau acetylation (at K343 and other sites) and tau accumulation, mediated by dysregulation of p300 acetyltransferase and SIRT1 deacetylase.

    “our recent study [2] suggested that TSC1 haploinsufficiency led to specific tau acetylation (at K343 and other sites) and tau accumulation, mediated by dysregulation of p300 acetyltransferase and SIRT1 deacetylase.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Alquezar C, Schoch KM, Geier EG, Ramos EM, Scrivo A, Li KH et al (2021) TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy. Sci Adv 7:eabg3897. https://doi.org/10.1126/sciadv.abg3897 source

  • May combine two claims.

    Premisecitation

    TSC has been linked to progressive neurodegeneration and FTD-like symptoms.

    “TSC has been linked to progressive neurodegeneration and FTD-like symptoms [12, 16].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA et al (2020) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol 77:358–366. https://doi.org/10.1001/jamaneurol.2019.4284 source

      The Discussion reports that adults with TSC had cognitive and behavioral impairments resembling FTD, supporting the FTD-like symptoms. But it says whether TSC predisposes to a neurodegenerative disorder requires further investigation; this study does not establish progressive neurodegeneration in TSC. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [16] Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0 source

  • May combine two claims.

    Findingown data

    Most of these tangles were accompanied by neuropil threads and concentrated in the limbic regions.

    “most of these tangles were accompanied by neuropil threads and concentrated in the limbic regions”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSC tauopathy shows no perivascular patterning, no predilection for sulcal depths, and little or no astroglial tauopathy.

    “In contrast to CTE, however, TSC tauopathy shows no perivascular patterning, no predilection for sulcal depths, and little (or no) astroglial tauopathy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In only one section did the authors identify astroglial tau inclusions, which were observed in the depth of a cortical sulcus.

    “In only one section did we identify astroglial tau inclusions, which were observed in the depth of a cortical sulcus”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immunoblotting generally corroborated the key immunohistochemical findings, including the consistency of tau acetylation across TSC tauopathy cases and the relative prominence of tau acetylation vs. phosphorylation, especially in the TSC1 mutation carrier.

    “Immunoblotting with a subset of the tau antibodies used for immunohistochemistry generally corroborated the key immunohistochemical findings (Figure 4), including the consistency of tau acetylation across TSC tauopathy cases and the relative prominence of tau acetylation vs. phosphorylation, especially in the TSC1 mutation carrier.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the three TSC tauopathy subjects, tau immunostaining was almost completely restricted to neurons, with NFTs located primarily in Layers 3 and 5, accompanied by a notable paucity of neuropil threads.

    “In these three TSC subjects, the tau immunostaining was almost completely restricted to neurons, with NFTs located primarily in Layers 3 and 5, accompanied by a notable paucity of neuropil threads.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Amyloid beta deposition, TDP-43 inclusions, and Lewy body disease were absent in all three screening brain regions in all three groups.

    “In all three groups, amyloid beta deposition (diffuse or neuritic plaques or vascular amyloid), TDP-43 inclusions, and Lewy body disease were absent in all three screening brain regions (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers.

    “The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    Genetic screening revealed 9 TSC2 carriers and one TSC1 mutation carrier; one subject had unknown genetic status due to lack of available frozen tissue.

    “Genetic screening revealed 9 TSC2 carriers and one TSC1 mutation carrier; one subject (TS 3) had an unknown genetic status due to lack of available frozen tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All of these features (balanced 3R/4R tauopathy, prominent neuropil threads, and detection with CP13, MC1, and p62) were absent in TSC tauopathy.

    “all of these features were absent in TSC tauopathy.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies reported that cortical tubers of infants with TSC-related intractable epilepsy exhibit phospho-tau immunoreactivity in dysmorphic neurons and glial cells, as well as in cellular processes in the neuropil.

    “Previous studies have reported that cortical tubers of infants with TSC-related intractable epilepsy exhibit phospho-tau immunoreactivity, in dysmorphic neurons (without frank neurofibrillary tangles) and glial cells, as well as in cellular processes in the neuropil [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Salminen A, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H, Alafuzoff I (2012) Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 96:87–95. https://doi.org/10.1016/j.pneurobio.2011.11.005 source

  • May combine two claims.

    Interpretationown data

    Unlike PART and AD, TSC tauopathy appears unlikely to begin in the medial temporal lobe, as it is most prominent in neocortical and paralimbic fronto-temporal-insular regions, amygdala, and ventral striatum.

    “Unlike PART and AD, which follow typical Braak stage topography, TSC tauopathy appears unlikely to begin in the medial temporal lobe, as it is most prominent in neocortical and paralimbic fronto-temporal-insular regions, amygdala, and ventral striatum.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TSC is caused by a pathogenic variant in either TSC1 or TSC2.

    “TSC is caused by a pathogenic variant in either TSC1 (coding for hamartin) located on chromosome 9q34 [23] or TSC2 (coding for tuberin) located on chromosome 16p13 [7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Togo T, Akiyama H, Iseki E, Uchikado H, Kondo H, Ikeda K et al (2004) Immunohistochemical study of tau accumulation in early stages of Alzheimer-type neurofibrillary lesions. Acta Neuropathol 107:504–508. https://doi.org/10.1007/s00401-004-0842-2 source
    • cites [7] European Chromosome 16 Tuberous Sclerosis C (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315. https://doi.org/10.1016/0092-8674(93)90618-z source

  • May combine two claims.

    Study design and conductown data

    The three groups did not differ in age or sex distribution.

    “As dictated by the study design, the three groups did not differ in age (F = 0.4, p = 0.6) or sex distribution (X2 = 1.7, p = 0.4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    One limitation of this study is the lack of detailed clinical information regarding the etiology, localization, and frequency of seizures in both groups.

    “One limitation of this study is the lack of detailed clinical information regarding the etiology, localization, and frequency of seizures in both groups”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The regional distribution, 3R and acetylated tau predominance, and inconspicuous or absent staining with CP13, MC1, and p62 combine to set TSC tauopathy apart.

    “The regional distribution, 3R and acetylated tau predominance, and inconspicuous or absent staining with CP13, MC1, and p62 combine to set TSC tauopathy apart.”
    Quote in the paperSubstantial claim
27 of 27

  • The paper relies on this without support.

    The non-TSC epilepsy control group adequately controls for recurrent seizures and other epilepsy-related factors despite the lack of quantitative seizure frequency information.

    “The purpose of the non-TSC epilepsy group was to ensure that changes observed in TSC were not merely the result of recurrent seizures, but quantitative seizure frequency information was not available.”

  • The paper relies on this without support.

    The clinical diagnosis of TSC in the NeuroBioBank subjects is accurate.

    “We searched the NIH NeuroBioBank for adults with a clinical diagnosis of TSC.”

  • The paper relies on this without support.

    The three TSC tauopathy cases are representative of TSC tauopathy in adults with TSC.

    “In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant “TSC tauopathy” not seen in epilepsy or non-neurological controls.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TSC is a distinct tauopathy characterized by AD-type mixed 3R/4R tau isoforms and absence of amyloid-β deposition.

    “Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.”

    From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [13]

    The Discussion says TSC tauopathy occurs without amyloid-beta deposition, supporting that part of the claim. But it distinguishes TSC tauopathy from AD: AD has a balanced 3R/4R pattern, whereas TSC tauopathy has more 3R than 4R tau. Calling its isoform pattern AD-type is therefore contrary to the paper. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Neuroimaging studies using tau-specific positron emission tomography radiotracers have demonstrated accumulation of flortaucipir (AV1451) in patients with TSC.

    “Neuroimaging studies using tau-specific positron emission tomography radiotracers have demonstrated accumulation of flortaucipir (AV1451) in patients with TSC, a tracer with high affinity for phosphorylated tau 181 (ptau-181) linked to AD.”

    From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [13]

  • Flortaucipir is well established to exhibit off-target binding.

    “This radioligand is well established to exhibit off-target binding (9, 12, 13).”

    From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [13]

    The Introduction mentions focal uptake on flortaucipir PET imaging, and the Discussion mentions a study of AV1451 (flortaucipir) staining. Neither passage addresses off-target binding. Searches for off-target binding and nonspecific tracer uptake found no passage in our copy that establishes the claim. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • The type of inclusion in FTD correlates well with brain regions involved, clinical symptomology, and the overall disease course of FTD.

    “The type of inclusion in FTD correlates well with brain regions involved, clinical symptomology, and the overall disease course of FTD.78”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [78]

    The Results section maps tau inclusions across brain regions in three people with TSC, but does not compare inclusion types in FTD or correlate them with symptoms or disease course (page unavailable). The Discussion says a progressive FTD-like syndrome with matching autopsy findings would be needed to classify TSC tauopathy as FTLD-tau. Searches for inclusion type, clinical phenotype, regional distribution, and disease course found no passage establishing the claimed correlations. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • EP 3 is listed as having both known and absent seizure-etiology data

    Minor

    EP 3 appears among the four patients with a known seizure etiology, then appears among those for whom etiology data were absent.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Hwang, J.-H. L., Perloff, O. S., Gaus, S. E., Benitez, C., Alquezar, C., Cosme, C. Q., Nana, A. L., Vatsavayai, S. C., Ramos, E. M., Geschwind, D. H., Miller, B. L., Kao, A. W., & Seeley, W. W.
Affiliations
  • University of California, San Francisco (US)
  • University of California, Los Angeles (US)
Corresponding author
Seeley, William W.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2022-12-05
Volume
145
Issue
1
Pages
1-12
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-022-02521-5
PMC
PMC10244026
OpenAlex
W4310676274
Cited by
15
References
27
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 2
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Tau Consortium
  • NIH (AG019724, AG062422, AG057195)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
tuberous sclerosis complex, tauopathy, neurofibrillary tangles, TSC1, TSC2, hamartin, tuberin, tau acetylation, tau phosphorylation, tau isoforms, neuropathology, frontotemporal dementia, epilepsy, post-translational modification
MeSH terms
Adult, Epilepsy, Humans, Mutation, Tuberous Sclerosis, Amyloid beta-Peptides, Tauopathies, Tumor Suppressor Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review