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Cited by 16Alzheimer's disease research and treatmentsTuberous Sclerosis Complex ResearchDementia and Cognitive Impairment Research

Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation

Open access
Liu, Andy J., Lusk, Jay B., Ervin, John, Burke, James, O’Brien, Richard, Wang, Shih-Hsiu J.·2022·Acta Neuropathologica Communications
DOI 10.1186/s40478-022-01330-xPMC PMC8896101
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Abstract

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems. Patients with TSC also experience neuropsychiatric symptoms collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorder (TAND). Due to research advancements in TSC, patients now live well beyond the age of 50. Many experience objective impairment of memory and executive function, supported by formal neuropsychological testing, beginning in their late 40s. Biomarker analysis has described elevated levels of phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET imaging has also shown focal accumulation of the radiotracer flortaucipir (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from accumulation of phosphorylated tau. However, the flortaucipir tracer has been reported to have significant off-target binding, preventing definitive conclusions from being drawn about the molecular etiology of neurodegeneration in TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir is bound to phosphorylated tau in brains of patients with TSC and further sought to determine the specific tau isoform seen in TSC. Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer’s disease. However, amyloid staining was negative in brains of adult patients with TSC. Therefore, we conclude that TAND symptoms are due to the accumulation of the phosphorylated tau isoform seen in Alzheimer’s disease. This study suggests that hyperactivation of the mammalian Target of Rapamycin pathway may play a role in the amyloid-independent development of 3R/4R tau aggregation. Our findings could lead to a new era of anti-tau therapies used to treat both disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

In adult tuberous sclerosis complex (TSC) brain tissue, flortaucipir (AV1451) labeled phosphorylated 3R/4R tau tangles that were also AT8- and GT38-positive, without amyloid plaques. Tangle density was sparse and lower than in Down syndrome/Alzheimer’s disease or FTLD-tau, supporting TSC/TAND as an amyloid-independent 3R/4R tauopathy.

Key findings

  • Among 35 cases (11 healthy controls, 9 DS/AD, 10 TSC, 5 FTLD-tau), TSC showed AT8 positivity in 5/10 (50%) entorhinal cortex and 5/10 (50%) BA8, but 0/10 in BA11; GT38 positivity was 5/10 (50%) in entorhinal cortex and BA8, and 4/10 (40%) in BA11; AV1451 positivity was 6/10 (60%) in entorhinal cortex and BA8, and 5/10 (50%) in BA11.
  • No TSC patients had amyloid-beta plaques by 4G8 staining, and no TSC patients exhibited glial-tau lesions such as coiled bodies, tufted astrocytes, or astrocytic plaques.
  • Semi-quantitative scores in TSC were sparse: median AT8 0.5 in BA8 and entorhinal cortex, 0 in BA11; median GT38 0.5 in BA8 and entorhinal cortex, 0 in BA11; median AV1451 1 in BA8 and entorhinal cortex, 0.5 in BA11. DS/AD and FTLD-tau had higher median scores, with AV1451 medians greater than 2 in all three regions.
  • AV1451 labeled neurofibrillary tangles in TSC, FTLD-tau, and DS/AD, and also labeled neuritic plaques in DS/AD; the authors conclude TSC is a novel amyloid-independent 3R/4R tauopathy and suggest mTOR hyperactivation may contribute to 3R/4R tau aggregation.

Methods

  • The CAPA study used formalin-fixed paraffin-embedded brain tissue from the NIH biobank: 35 patients total (11 healthy controls, 9 DS/AD, 10 TSC, 5 FTLD-tau), with controls age- and gender-matched; AD tissue was requested with Braak stage 4 and above, and three subjects had Down syndrome.
  • Three brain regions were analyzed: dorsolateral prefrontal cortex (Brodmann area 8), inferior frontal cortex (Brodmann area 11), and entorhinal cortex.
  • Immunohistochemistry used AT8 (pTau Ser202/Thr205), GT38 (3R/4R tau conformation), and 4G8 (amyloid-beta); AV1451 was applied as a fluorescent PET ligand. Five 1 mm² fields with the highest tangle counts per slide were scored semi-quantitatively from 0 to 5.

Limitations

  • Stated: the sample size was small because TAND is rare, preventing formal tests of statistical significance; the study could not control for intellectual ability/cognitive status, which has been suggested as a major risk factor for TAND clinical presentation.
  • Evident from the text: the study is cross-sectional autopsy tissue limited to three brain regions, with small diagnostic subgroups, and it does not directly test whether mTOR signaling causes tau aggregation.

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

Integrity signals

Registry

Crossref · 10.1186/s40478-022-01330-x

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

8 of 10 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    Hyperactivation of mTOR signaling seen in TSC could contribute to increased tau protein aggregation and the development of 3R/4R positive tangles.

    “In particular, the hyperactivation of mTOR signaling seen in TSC could contribute to increased tau protein aggregation and the development of 3R/4R positive tangles.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Cai Z, Chen G, He W, Xiao M, Yan L-J (2015) Activation of mTOR: a culprit of Alzheimer’s disease? Neuropsychiatr Dis Treat 11:1015–1030. https://doi.org/10.2147/NDT.S75717 source

      The section “The activation of mTOR: an enhancer of the hyperphosphorylation of tau?” (page unavailable) says mTOR activation promotes tau pathology and neurofibrillary-tangle formation. It discusses this in the context of Alzheimer’s disease, not TSC, and does not identify the tangles as 3R/4R positive. The TSC-specific and 3R/4R parts of the claim are therefore unsupported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [7] Mueed Z, Tandon P, Maurya SK, Deval R, Kamal MA, Poddar NK (2019) Tau and mTOR: the hotspots for multifarious diseases in Alzheimer’s development. Front Neurosci 12:1017. https://doi.org/10.3389/fnins.2018.01017 source

      The “AMPK and mTOR” section says that inactivation of the TSC1/TSC2 complex activates an upstream regulator of mTOR, while “mTOR and Tau” links mTOR activation to tau pathology and neurofibrillary tangles. The paper does not establish this process in people with tuberous sclerosis or identify the tangles as 3R/4R positive. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • Rests on an assumption: TSC1/TSC2 mutations cause hyperactivation of the mTOR pathway.
  • Study design and conductnone given

    The study was unable to control for intellectual ability/cognitive status.

    “Additionally, this study was unable to control for intellectual ability/cognitive status, which has been suggested to be a major risk factor for the clinical presentation of TAND [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D’Amato L, Beaure d’ Augères G, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, Nabbout R, O’Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Kingswood JC, Jansen AC, Investigators T, Shinohara N, Horie S, Kubota M, Tohyama J, Imai K, Kaneda M, Kaneko H, Uchida Y, Kirino T, Endo S, Inoue Y, Uruno K, Serdaroglu A, Yapici Z, Anlar B, Altunbasak S, Lvova O, Belyaev OV, Agranovich O, Levitina EV, Maksimova YV, Karas A, Jiang source
  • Interpretationreasoning

    PART is unlikely to explain the findings in the TSC cohort.

    “For these reasons, PART is unlikely to explain our findings in the TSC cohort.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Bell WR, An Y, Kageyama Y, English C, Rudow GL, Pletnikova O, Thambisetty M, O’Brien R, Moghekar AR, Albert MS, Rabins PV, Resnick SM, Troncoso JC (2019) Neuropathologic, genetic, and longitudinal cognitive profiles in primary age-related tauopathy (PART) and Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 15:8–16. https://doi.org/10.1016/j.jalz.2018.07.215 source

      The Discussion (> PART and AD; page not available) describes PART’s pathology and cognitive profile relative to Alzheimer’s disease, but does not assess a TSC cohort. The Methods (> Clinical cohorts and cognitive assessment; page not available) identifies the study cohorts as BLSA and Johns Hopkins participants. Searches for TSC and for the proposed explanation found no passage addressing whether PART explains the citing authors’ findings. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The selected brain regions (BA8, BA11, entorhinal cortex) are sufficient to characterize TAND-related tau pathology.
  • Findingown data

    Patients with AD and FTLD had high median GT38 scores in all three brain regions.

    “Patients with AD and FTLD had high median GT38 scores in all three brain regions.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer's disease.

    “Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer’s disease.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 6
  • May combine two claims. 15

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

    Premisecitation

    TSC is a neurodevelopmental disorder arising primarily from mutations in TSC1 (hamartin) and TSC2 (tuberin).

    “Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder arising primarily from mutations in TSC1 (hamartin) and TSC2 (tuberin) (TSC1/2) [8].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Northrup H, Krueger DA, Roberds S, Smith K, Sampson J, Korf B, Kwiatkowski DJ, Mowat D, Nellist M, Povey S, de Vries P, Byars A, Dunn D, Ess K, Hook D, Jansen A, King B, Sahin M, Whittemore V, Thiele E, Bebin EM, Chugani HT, Crino P, Curatolo P, Holmes G, Nabbout R, O’Callaghan F, Wheless J, Wu J, Darling TN, Cowen EW, Gosnell E, Hebert A, Mlynarczyk G, Soltani K, Teng J, Wataya-Kaneda M, Witman PM, Kingswood C, Bissler J, Budde K, Hulbert J, Guay-Woodford L, Sauter M, Zonneberg B, Jóźwiak S, Bartels U, Berhouma M, Franz DN, Koenig MK, Roach ES, Roth J, Wang H, Weiner H, McCormack FX, Almoosa source

      The Introduction identifies TSC1 and TSC2 as the two causative genes, and Genetic diagnostic criteria says a pathogenic mutation in either is sufficient for diagnosis. The copy does not identify their proteins as hamartin and tuberin. Its Introduction describes TSC as a disease affecting virtually any organ; the Central nervous system features section describes developmental brain abnormalities, but does not classify TSC as a neurodevelopmental disorder. No page numbers were provided for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CSF pTau-181 levels are elevated in TSC subjects compared to healthy controls, with an average of 32 pg/mL.

    “Cerebrospinal fluid (CSF) results showed elevated phosphorylated tau (pTau-181) levels with an average of 32 pg/mL in TSC subjects when compared to healthy controls [5].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA, La Joie R, Fong JC, Taylor J, Karydas A, Ramos EM, Coppola G, Boxer AL, Rabinovici GD, Miller BL, Kao AW (2019) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2019.4284 source

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

    Premisecitation

    Patients with TSC frequently suffer from behavioral, cognitive and psychiatric difficulties collectively termed TAND.

    “In addition to the physical manifestations of TSC, these patients frequently suffer from behavioral, cognitive and psychiatric difficulties collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric disorders (TAND) [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] De Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC, Hook D, King BH, Sahin M, Jansen A (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

  • Classified as probably not a substantial claim.

    Premisecitation

    AV1451 has a high affinity for pTau-181 related to Alzheimer's disease by PET imaging.

    “AV1451 has a high affinity for pTau-181 related to Alzheimer’s disease by PET imaging [6]; however, AV1451 also displays significant off-target binding [1].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Mattsson N, Schöll M, Strandberg O, Smith R, Palmqvist S, Insel PS, Hägerström D, Ohlsson T, Zetterberg H, Jögi J, Blennow K, Hansson O (2017) 18 F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol Med 9:1212–1223. https://doi.org/10.15252/emmm.201707809 source

      The Introduction (page unavailable) describes 18F-AV-1451 as a PET tracer that detects Alzheimer’s disease–type tau aggregates. The Discussion (page unavailable) reports high affinity for AD-type tau lesions, but neither passage establishes high affinity specifically for pTau-181. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    TSC patients exhibited sparsely positive AT8 staining in the entorhinal cortex and BA8 but not BA11.

    “Patients with TSC exhibited sparsely positive AT8 staining in the entorhinal cortex and BA8 but not BA11.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TSC patients had a median GT38 score of 0.5 in the entorhinal cortex, with a 75th percentile score of 2.

    “the median GT38 score in entorhinal cortex was 0.5, whitle the 75th percentile score was 2, as some patients had scores up to 4 (6–10 tangles /1mm2 field).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSC patients had a median AT8 score of 0.5 in the entorhinal cortex, with a 75th percentile score of 1.75.

    “The median AT8 score for patients with TSC was also 0.5 in the entorhinal cortex, but the 75th percentile score was 1.75, as more patients had AT8 scores of 2 (1–2 tangles/1 mm2 field) or 3 (3–5 tangles/1 mm2 field).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSC patients had a median GT38 score of 0 in BA11, with a 75th percentile score of 1.

    “For GT38 scoring (Fig. 2B), while the median GT38 score in BA11 for patients with TSC was 0, the 75th percentile score was 1 (< 1 tangle/1 mm2 field), as several patients had scores of 1 or 2 (1–2 tangles/1mm2 field).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSC patients exhibited more strongly positive GT38 staining in all three brain regions studied, although density was sparse compared to DS/AD or FTLD-tau patients.

    “Patients with TSC exhibited more strongly positive GT38 (3R tau + 4R tau) staining in all three brain regions studied, although the density was still sparse compared to patients with DS/AD or FTLD-tau (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TSC patients had median AV1451 scores of 0.5, 1, and 1 in BA11, BA8, and the entorhinal cortex respectively, compared to control patients with a median score of 0 in all regions.

    “Patients with TSC had median scores of 0.5, 1, and 1 in BA11, BA8, and the entorhinal cortex respectively, compared to control patients with a median score of 0 in all regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AV1451 also labeled neuritic plaques from DS/AD patients, but no glial tau lesions were observed.

    “AV1451 also labeled neuritic plaques from patients with DS/AD, but no glial tau lesions were observed (Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSC patients had a median GT38 score of 0.5 in BA8, with a 75th percentile score of 1.

    “The median GT38 score in BA8 was 0.5, and the 75th percentile score was 1;”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TSC patients lacked amyloid plaques and glial-tau lesions, distinguishing the pathology underlying TAND from other neurodegenerative conditions.

    “Patients with TSC notably lacked amyloid plaques and glial-tau lesions, distinguishing the pathology underlying TAND from other neurodegenerative conditions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The absence of amyloid plaques in the sampled brain regions indicates that the tauopathy is amyloid-independent.

  • May combine two claims.

    Interpretationown data

    TSC patients had elevated density of AT8 staining compared to controls, but less than AD or FTLD patients, suggesting that phosphorylated tau accumulates to some extent in TSC.

    “Our finding that patients with TSC had elevated density of AT8 staining, which identifies tau phosphorylated at Ser202 and/or Thr205, compared to control patients, but less than patients with AD or FTLD suggests that phosphorylated tau accumulates to some extent in patients with TSC.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem immunohistochemical staining with AT8, GT38, and AV1451 accurately reflects the presence and isoform composition of phosphorylated tau in the patients' brains.

  • May combine two claims.

    Premisecitation

    TSC is an infantile tauopathy accumulating phosphorylated tau.

    “This is based on prior studies which have shown that TSC is an infantile tauopathy accumulating phosphorylated tau [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 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

  • May combine two claims.

    Interpretationown data

    TSC is a genetic 3R/4R tauopathy that develops independent of amyloid plaques seen in AD.

    “These results suggest that TSC is a genetic 3R/4R tauopathy that develops independent of amyloid plaques seen in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem immunohistochemical staining with AT8, GT38, and AV1451 accurately reflects the presence and isoform composition of phosphorylated tau in the patients' brains.
    • Rests on an assumption: The TSC brain tissue samples are representative of adult TSC patients with TAND.
    • Rests on an assumption: The absence of amyloid plaques in the sampled brain regions indicates that the tauopathy is amyloid-independent.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The study performed detailed, semi-quantitative neuropathological evaluation of various tau isoforms.

    “Additional strengths include detailed, semi-quantitative neuropathological evaluation of various tau isoforms, allowing for precise definition of the specific tauopathy seen in patients with TAND.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Despite limitations, the study suggests that TAND is a novel 3R/4R tauopathy independent of amyloid plaque formation.

    “Despite these limitations, this study suggests that TAND is a novel 3R/4R tauopathy independent of amyloid plaque formation, and points to promising new directions for research into the mechanism of TAND symptoms and novel anti-tau therapies in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem immunohistochemical staining with AT8, GT38, and AV1451 accurately reflects the presence and isoform composition of phosphorylated tau in the patients' brains.
    • Rests on an assumption: The TSC brain tissue samples are representative of adult TSC patients with TAND.
    • Rests on an assumption: The absence of amyloid plaques in the sampled brain regions indicates that the tauopathy is amyloid-independent.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The study compared TSC patients to age and gender matched healthy controls.

    “Strengths of this study include its comparison to age and gender matched healthy controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The density of GT38 positive tangles was higher in TSC patients than controls, and lower than AD/FTLD patients, suggesting that TSC is a mixed 3R/4R tauopathy.

    “Additionally, our finding that the density of GT38 positive tangles was higher in patients with TSC than control patients, and again lower than patients with AD/FTLD, suggests that TSC is a mixed 3R/4R tauopathy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem immunohistochemical staining with AT8, GT38, and AV1451 accurately reflects the presence and isoform composition of phosphorylated tau in the patients' brains.

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

    Study design and conductnone given

    The study simultaneously evaluated multiple neuropathologies, including AD, TSC, FTLD-tau, and other neurodegenerative disorders.

    “as well as its simultaneous evaluation of multiple neuropathologies, including AD, TSC, FTLD-tau, and other neurodegenerative disorders.”
    Quote in the paperNot a substantial claim
21 of 21

  • The paper relies on this without support.

    TSC1/TSC2 mutations cause hyperactivation of the mTOR pathway.

    “These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems.”

  • The paper relies on this without support.

    Postmortem immunohistochemical staining with AT8, GT38, and AV1451 accurately reflects the presence and isoform composition of phosphorylated tau in the patients' brains.

    “The antibodies used for this study were AT8 (ThermoScientific cat # MN1020), GT-38 (ABCAM cat # ab254274), and 4G8 (BioLegend Cat#: 800,702).”

  • The paper relies on this without support.

    The TSC brain tissue samples are representative of adult TSC patients with TAND.

    “Tissue from cognitively healthy controls (HC), and from patients with AD, FTLD-tau, and TSC were obtained from the NIH biobank.”

  • The paper relies on this without support.

    The absence of amyloid plaques in the sampled brain regions indicates that the tauopathy is amyloid-independent.

    “Furthermore, no patients with TSC had amyloid-beta plaques (Fig. 4).”

  • The paper relies on this without support.

    The selected brain regions (BA8, BA11, entorhinal cortex) are sufficient to characterize TAND-related tau pathology.

    “Since patients with TAND showed executive function, behavioral and memory difficulties, three brain areas involving these functions, the dorsolateral prefrontal cortex (Brodmann area 8), inferior Frontal Cortex (Brodmann area 11) and the entorhinal cortex were selected for neuropathological analysis.”
5 of 5

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?

  • 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.”

    From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [11]

    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

  • Beginning in mid-to-late adulthood, a subset of individuals with TSC demonstrate cognitive decline that clinically overlaps with Alzheimer's disease dementia.

    “Notably, beginning in mid-to-late adulthood, a subset of individuals with TSC demonstrate cognitive decline that clinically overlaps with Alzheimer's disease (AD) dementia (8-10).”

    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 [8]

    The Abstract reports that many patients with TSC experience objectively measured memory and executive-function impairment beginning in their late 40s. The Introduction links significant memory loss to a hypothesis that TSC may resemble the tauopathy seen in AD, but describes the reported clinical overlap as being with frontotemporal dementia; it does not establish clinical overlap with AD dementia. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Neuropathological studies in adults with TSC showed sparse neurofibrillary tangles that stain with both AV1451 and GT-38 in the absence of insoluble amyloid-β deposition.

    “Subsequently, complementary neuropathological studies in adults with TSC showed sparse neurofibrillary tangles that stain with both AV1451 and GT-38.GT-38 is an antibody that detects mixed 3R/4R isoforms of tau seen in AD, in the absence of insoluble amyloid-β deposition (8).”

    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 [8]

  • 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 [8]

  • 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].”

    From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [11]

Self-check

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

  • TSC undetermined-IDD percentage uses the wrong denominator

    Minor

    Table 1 reports 2 of 10 TSC patients with undetermined IDD status as 22%; that is 20%.

    Reported 22 · recomputed 20

  • TSC intellectual-disability percentage uses the wrong denominator

    Minor

    Table 1 reports 5 of 10 TSC patients with IDD as 55%; that is 50%. The Results text also repeats the 55% figure.

    Reported 55 · recomputed 50

  • TSC IDD-absent percentage uses the wrong denominator

    Minor

    Table 1 reports 3 of 10 TSC patients without IDD as 33%; that is 30%.

    Reported 33 · recomputed 30

3 of 3

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Related

Authors
Liu, A. J., Lusk, J. B., Ervin, J., Burke, J., O’Brien, R., & Wang, S.-H. J.
Affiliations
Duke University (US)
Corresponding author
Liu, Andy J.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2022-03-03
Volume
10
Issue
1
Pages
27-27
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-022-01330-x
PMC
PMC8896101
OpenAlex
W4214858690
Cited by
15
References
14
Citations by year
2026: 2 · 2024: 3 · 2023: 6 · 2022: 4
FWCI
1.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tuberous sclerosis complex, tauopathy, phosphorylated tau, flortaucipir, tau PET imaging, off-target binding, TSC1, TSC2, mTOR signaling, tau aggregation, anti-tau therapy
MeSH terms
Adult, Alzheimer Disease, Amyloidosis, Humans, Tuberous Sclerosis, Protein Isoforms, Tauopathies, Amyloidogenic Proteins, TOR Serine-Threonine Kinases

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 ›

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