Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease

In the paper

“Interestingly, evidence from AD neuronal culture models indicate that soluble Aβ oligomers (AβOs) induce tau hyperphosphorylation in multiple sites.16,17”

What the sources say

• Supported

  The Discussion reports that soluble Aβ oligomers induced tau hyperphosphorylation at five AD-characteristic epitopes in cultured neurons. The Results section 3.6 also reports increased tau phosphorylation in hippocampal neuronal cultures treated with soluble AD-brain extract containing Aβ oligomers. (LLM, conf=0.94)

  cites [16] De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging source
• Disputed

  The Discussion reports increased tau phosphorylation at Ser208 after oligomeric Aβ exposure, but says other canonical tau phosphorylation sites were not remarkably altered after 24 hours. Its finding is therefore contrary to the attributed claim of hyperphosphorylation at multiple sites. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [17] Sackmann, 2020, Oligomeric amyloid-beta induces early and widespread changes to the proteome in human iPSC-derived neurons, Sci Rep sourceExperimental — accuracy not yet measured

In the paper

“Specifically, CSF concentrations of t-tau and p-tau are proposed to reflect neurodegeneration and tau pathology in the form of NFTs, respectively.7”

What the sources say

• Supported

  Section 9.3 says CSF T-tau reflects the intensity of neuronal damage, while elevated CSF P-tau reflects a pathologic state associated with paired-helical-filament tau formation. This supports the proposed distinction. Section 9.1 clarifies that CSF P-tau is not a direct measure of accumulated tau deposits. (LLM, conf=0.90)

  cites [7] Jack, 2018, NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease, Alzheimers Dement source

In the paper

“Recent reports have suggested that CSF p-tau217 might better discriminate AD from other neurodegenerative diseases24,27, 28, 29, 30 than CSF p-tau181.”

What the sources say

• Supported

  The Results section, “Diagnostic accuracy of CSF p-tau217 and p-tau181,” reports that p-tau217 had a significantly higher AUC than p-tau181 for distinguishing AD dementia from non-AD neurodegenerative disorders. The Discussion states the same conclusion directly; the citing sentence’s cautious “might” does not overstate it. (LLM, conf=0.95)

  cites [24] Janelidze, 2020, Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease, Nat Commun source
• Supported

  The Results section (Montpellier AD cohort) reports that pT181 values overlapped between AD and non-AD patients with disorders including PSP, LBD, and FTLD, whereas pT217 values strongly discriminated between the groups. The Conclusions also describe pT217 as a more accurate biomarker than pT181, consistent with the citing sentence’s cautious wording. (LLM, conf=0.94)

  cites [27] Barthelemy, 2020, Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification, Alzheimers Res Ther source
• Supported

  The Introduction and Discussion report that earlier studies suggested p-tau217 could distinguish AD from non-AD disorders better than p-tau181, supporting the citing sentence’s hedged description of recent reports. This paper’s own head-to-head Results found similar accuracy for the biomarkers in distinguishing AD dementia from non-AD dementia; page numbers were not supplied. (LLM, conf=0.86)

  cites [28] Karikari, 2020, Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis, Alzheimers Dement source
• Supported

  The Background states that multiple studies suggest CSF p-tau217 is better than p-tau181 at distinguishing AD from non-AD neurodegenerative diseases. It also notes that the advantage may depend on the p-tau181 antibodies used, which is consistent with the citing sentence’s cautious wording. (LLM, conf=0.92)

  cites [29] Mielke, 2021, Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline, Alzheimers Dement source
• Supported

  The paper’s background explicitly states that CSF p-tau217 more accurately distinguished AD dementia from non-AD neurodegenerative disorders than p-tau181. Its Discussion also reports greater discriminative accuracy for p-tau217 than the p-tau181 assays tested. (LLM, conf=0.93)

  cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology source

In the paper

“In addition, CSF p-tau217 correlates better with Aβ and tau PET imaging than CSF p-tau181.24,30”

What the sources say

• Supported

  The Discussion states that CSF p-tau217 had higher correlations than p-tau181 with [18F]flortaucipir (tau PET) and [18F]flutemetamol (amyloid-β PET) retention. The Results section also reports significantly higher correlation coefficients for p-tau217 across the tau PET regions studied. Page numbers were not supplied in the passages. (LLM, conf=0.94)

  cites [24] Janelidze, 2020, Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease, Nat Commun source
• Supported

  The Results section (‘Correlations Between CSF P-Tau and Aβ and Tau-PET’) reports stronger correlations for CSF p-tau217Lilly than for the tested p-tau181 assays with both Aβ-PET and tau-PET. The Discussion explicitly summarizes the same comparison. The finding is based on the assays and participant groups studied, rather than every possible p-tau assay or population. (LLM, conf=0.94)

  cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology source

In the paper

“We have recently reported that CSF p-tau231 increases early in the AD continuum and, therefore, may detect preclinical AD among cognitively unimpaired (CU) individuals.31”

What the sources say

• Supported

  The Discussion reports that CSF Mid-p-tau231 increases prominently early in the Alzheimer’s continuum, including when Aβ pathology is subtle. It also reports that the biomarker differentiates Aβ-positive from Aβ-negative cognitively unimpaired individuals, supporting the hedged claim that it may detect preclinical AD. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [31] Suarez-Calvet, 2020, Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Abeta pathology are detected, EMBO Mol Med source

In the paper

“However, these biomarkers remain at normal concentrations in other neurodegenerative disorders with substantial neurodegeneration,8, 9, 10 and also those with tau pathology.11, 12, 13”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Riemenschneider, 2003, Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias, Mol Psychiatry source
• ?Not checked — no full text of the sourcecites [9] Skillback, 2014, Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish mortality registry, JAMA Neurol source
• ?Not checked — no full text of the sourcecites [10] Schoonenboom, 2012, Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort, Neurology source
• ?Not checked — no full text of the sourcecites [11] Hampel, 2004, Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study, Arch Gen Psychiatry source
• ?Could not verify

  The Introduction (page unavailable) says that tau pathology occurs in non-Alzheimer neurodegenerative disorders, and the Conclusions (page unavailable) discuss the diagnostic performance of CSF p-tau181. Neither passage establishes that CSF t-tau and p-tau remain at normal concentrations in those disorders, including those with tau pathology. Searches for their concentrations in non-Alzheimer disorders did not find that result in our copy. (LLM, conf=0.73)

  cites [12] Leuzy, 2020, Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders, JAMA Neurol sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (page unavailable) reports that CSF p-tau distinguishes Alzheimer disease from non-AD neurodegenerative conditions, lending support to a difference in biomarker levels. It does not establish that both p-tau and t-tau remain at normal concentrations in disorders with tau pathology; that stronger, disorder-specific claim is unsupported by the passages in our copy. (LLM, conf=0.76)

  cites [13] La Joie, 2018, Associations between [(18)F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample, Neurology sourceExperimental — accuracy not yet measured

In the paper

“a recent study in transgenic mice suggests that early removal of Aβ seeds, before Aβ deposition becomes detectable, led to a significant reduction of Aβ accumulation and downstream pathologies.32”

What the sources say

• Supported

  The Discussion reports that targeting Aβ seeds before amyloid formation was detectable significantly reduced Aβ deposition and associated pathologies six months later in a mouse model. The Abstract likewise reports reduced deposition and downstream pathologies after antibody treatment at the pre-amyloid stage. (LLM, conf=0.94)

  cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci source

In the paper

“Thus, it is suggested that CSF p-tau biomarkers likely indicate an active process of tau secretion, and one that is correlated with cerebral Aβ deposition in early disease.20, 21, 22”

What the sources say

• Partly supported

  The Methods (Biochemical Analysis; page unavailable) say the study measured CSF phosphorylated tau. The Results (Combined Model; page unavailable) place increased CSF tau and cerebral Aβ deposition about 15 years before expected symptom onset in mutation carriers. These findings support their early co-occurrence, but the paper does not establish active tau secretion or a correlation specifically between CSF p-tau and cerebral Aβ deposition. (LLM, conf=0.82)

  cites [20] Bateman, 2012, Clinical and biomarker changes in dominantly inherited Alzheimer's disease, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion (page unavailable) report that low baseline CSF Aβ1–42 was associated with subsequent increases in CSF p-tau181, supporting a relationship between the biomarkers in the studied cohort. They do not establish that p-tau indicates active tau secretion or directly show a correlation with cerebral Aβ deposition; the association measured here was with CSF Aβ1–42. (LLM, conf=0.86)

  cites [21] Toledo, 2013, Longitudinal change in CSF Tau and Abeta biomarkers for up to 48 months in ADNI, Acta Neuropathol sourceExperimental — accuracy not yet measured
• Partly supported

  The Cell-to-cell transfer of tau section says CSF in AD contains elevated phosphorylated tau and that active cellular processes contribute to tau secretion. The paper also discusses amyloid pathology as a possible trigger for tau release, but it does not state that CSF p-tau biomarkers correlate with cerebral Aβ deposition in early disease. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [22] Brunello, 2020, Mechanisms of secretion and spreading of pathological tau protein, Cell Mol Life Sci sourceExperimental — accuracy not yet measured

In the paper

“Our data, like prior studies,18,28,31 shows an increase of CSF p-tau epitopes in the preclinical phase of the disease, prior to symptom onset and before substantial tau PET ligand retention.”

What the sources say

• Supported

  The Discussion reports an early rise in CSF pT217/T217 and pT181/T181 before clinical symptoms. Extended Data Fig. 6 reports little tau-PET elevation until estimated symptom onset in dominantly inherited Alzheimer’s disease, placing the soluble p-tau increase before substantial tau-PET retention. (LLM, conf=0.93)

  cites [18] Barthelemy, 2020, A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease, Nat Med source
• Partly supported

  The Introduction reports that CSF p-tau217 begins to increase in preclinical familial Alzheimer’s disease, supporting an increase before symptoms. The Discussion also describes early increases in N-terminal p-tau biomarkers. Neither passage establishes that these increases precede substantial tau-PET ligand retention; the Introduction reports a correlation with tau-PET, not that timing. (LLM, conf=0.84)

  cites [28] Karikari, 2020, Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis, Alzheimers Dement sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that CSF p-tau increases earlier in Alzheimer’s disease than tau PET, citing prior timing studies. The study’s Conclusion reports increases in several CSF p-tau biomarkers in cognitively unimpaired people at an early preclinical stage. Tau PET timing is discussed rather than directly measured in this study. (LLM, conf=0.90)

  cites [31] Suarez-Calvet, 2020, Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Abeta pathology are detected, EMBO Mol Med source

In the paper

“P-tau231 levels in blood have also recently been demonstrated to increase earlier than p-tau18160 (Tissot et al., 2022), however, a direct comparison with p-tau217 in early preclinical disease is not currently available.”

What the sources say

• Supported

  The ‘Plasma p-tau231 as an early markers of AD pathology’ section reports that plasma p-tau231 increased earlier than plasma p-tau181 as a function of Aβ deposition. The Discussion explicitly says the study could not directly compare plasma p-tau231 with plasma p-tau217; its p-tau217 comparison used CSF instead. (LLM, conf=0.93)

  cites [60] Ashton, 2021, Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology, Acta Neuropathol source
• ?Not matched

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

  cites Tissot et al., 2022

In the paper

“Thus, in relation to sporadic AD, this study adds further support to the hypothesis that CSF p-tau is closely related to Aβ-mediated tau release from neurons19 and challenges the notion of being simply a state marker of NFT.”

What the sources say

• Partly supported

  The Results section reports that CSF tau production, including synthesis and release, correlates with amyloid burden; the Discussion proposes that this increase can precede tau aggregation. But the amyloid–release analysis concerns tau overall, not specifically CSF p-tau, and it does not establish that Aβ causes neuronal p-tau release. The paper therefore supports the broader hypothesis, but not the claim at that level of specificity. (LLM, conf=0.84)

  cites [19] Sato, 2018, Tau kinetics in neurons and the human central nervous system, Neuron sourceExperimental — accuracy not yet measured

In the paper

“Previous neuropathological findings, which motivated the CSF assay development of p-tau231, highlighted that a key component of pre-tangle pathology was phosphorylation at threonine 23155 and that CSF p-tau231 is an important discriminant of Braak 0-I from more advanced Braak stages.56”

What the sources say

• ?Not checked — no full text of the sourcecites [55] Augustinack, 2002, Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease, Acta Neuropathol source
• Partly supported

  The Discussion links pT231 to pre-tangle structures, and the Results report higher pT231 in brain tissue at Braak III–IV than at Braak 0–I. The paper also says CSF pT231 is increased in AD patients, but it does not show that CSF p-tau231 discriminates between Braak stages; its Braak comparison used brain tissue. In the citing sentence, the citation to this paper is attached to the CSF discrimination claim. (LLM, conf=0.84)

  cites [56] Ercan-Herbst, 2019, A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer's disease brain, Acta Neuropathol Commun sourceExperimental — accuracy not yet measured

In the paper

“[18F]MK6240 detects paired helical filament (PHF) tau and has shown a high binding affinity for brain homogenate rich in NFTs.61”

What the sources say

• Partly supported

  The Introduction reports high affinity of MK6240 for NFT-rich brain homogenate, and the paper’s binding assays support high affinity for tau deposits in Alzheimer’s disease tissue. The copy describes binding to tau fibrils but does not specifically identify the detected tau as paired helical filament (PHF) tau. Its own tissue-binding experiments used 3H-MK6240 rather than 18F-MK6240. (LLM, conf=0.84)

  cites [61] Malarte, 2020, Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer's disease cases, Eur J Nucl Med Mol Imaging sourceExperimental — accuracy not yet measured

In the paper

“Tau phosphorylation at threonine 231 is one of the earliest events in the cascade of phosphorylation,57 that modulates tubulin assembly.58”

What the sources say

• Partly supported

  In “Tau protein phosphorylation and hyperphosphorylation” (page unavailable), the paper discusses phosphorylated tau at the Thr231 proline motif, but does not say Thr231 phosphorylation is among the earliest events in a phosphorylation cascade. “Normal tau function” (page unavailable) says tau promotes tubulin polymerization, but does not link that effect specifically to Thr231 phosphorylation; the citing sentence attaches a separate citation to its assembly clause. (LLM, conf=0.78)

  cites [57] Castellani, 2019, Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges, J Alzheimers Dis sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] Amniai, 2009, Alzheimer disease specific phosphoepitopes of Tau interfere with assembly of tubulin but not binding to microtubules, FASEB J source

In the paper

“Thus, one could propose that increases in CSF p-tau231 are related to early Aβ seeds and could act as a key biomarker for the recently described “pre-amyloid phase” of AD, which occurs before Aβ deposition threshold.32”

What the sources say

• Supported

  The citation supports the description of a pre-amyloid phase, not the citing authors’ proposed role for CSF p-tau231. The Discussion (page unavailable) describes Aβ seeds before amyloid formation is detectable; the Results place an increase in insoluble Aβ before deposits become detectable by histology or PET. (LLM, conf=0.90)

  cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci source

In the paper

“Specifically, CSF p-tau231 becomes abnormal first and seems the principal p-tau candidate to identify early Aβ seeds in the recently proposed “pre-amyloid phase”,32 which is currently seen as the optimal period for therapeutic intervention.”

What the sources say

• Partly supported

  The Abstract and Discussion describe a pre-amyloid phase with targetable Aβ seeds and propose intervention before detectable deposition, based on a mouse model. They do not establish that CSF p-tau231 becomes abnormal first or is the principal marker of those seeds; the Discussion also says the efficacy of early seed removal in humans has not been established. (LLM, conf=0.88)

  cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci sourceExperimental — accuracy not yet measured

In the paper

“CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages of disease11,49, 50, 51, 52, 53 but often it has been concluded these changes are not different from CSF p-tau181 when directly compared.54”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Hampel, 2004, Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study, Arch Gen Psychiatry source
• ?Not checked — no full text of the sourcecites [49] Santos, 2019, Validation of a prototype tau Thr231 phosphorylation CSF ELISA as a potential biomarker for Alzheimer's disease, J Neural Transm source
• Partly supported

  The Introduction reports that one meta-analysis found P-tau181 and P-tau231 comparably good for AD diagnosis, supporting the claim that a direct comparison has found them similar. But it does not establish that this was often concluded, and the paper’s Discussion concludes that P-tau231 was superior at separating AD patients from normal controls. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [50] Spiegel, 2016, Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease, J Alzheimers Dis sourceExperimental — accuracy not yet measured

In the paper

“Increases in CSF p-tau occur before both tau PET20,63,64 and established measures of neuronal death (e.g., neurofilament light, magnetic resonance imaging or [18F]FDG PET), thus CSF p-tau cannot merely reflect NFT leakage from dying neurons.”

What the sources say

• Partly supported

  The Results (Biochemical Measures and Combined Model; page not provided) report increased CSF tau about 15 years before expected symptom onset, preceding FDG-PET hypometabolism at about 10 years. But brain atrophy was detected at the same time as increased CSF tau, not later. The paper measured phosphorylated tau but does not establish the claimed sequence relative to tau PET or neurofilament light, or the conclusion about NFT leakage. (LLM, conf=0.87)

  cites [20] Bateman, 2012, Clinical and biomarker changes in dominantly inherited Alzheimer's disease, N Engl J Med sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to the tau PET portion of the sentence. The Results section ('Longitudinal CSF tau levels increase in preclinical AD before Tau PET becomes positive'; page not supplied) reports rising CSF p-tau in amyloid-positive, cognitively unimpaired people whose later tau PET scans were almost all negative. The sentence does not attach this citation specifically to the separate claim about measures of neuronal death. (LLM, conf=0.94)

  cites [63] Mattsson-Carlgren, 2020, Abeta deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease, Sci Adv source
• Partly supported

  The Discussion says CSF measures of tauopathy likely become abnormal before tau PET measures, supporting the timing comparison to which this citation is attached. It also says the timing results are qualitative and that larger studies are needed to establish the order definitively; the citing sentence states that order as fact. (LLM, conf=0.86)

  cites [64] Gordon, 2019, Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers, Brain sourceExperimental — accuracy not yet measured

In the paper

“While no statistical superiority was demonstrated for p-tau217 over p-tau231, we did observe higher fold changes between AD and all other clinical groups for p-tau217 which is consistent with more recent findings.30”

What the sources say

• Supported

  The Results section (CSF P-Tau Levels by Diagnostic Group; page unavailable) reports larger fold increases for p-tau217 than p-tau231 across the diagnostic groups it compares. The statement that the citing authors found no statistical superiority describes their own analysis, not a finding attributed to this source. (LLM, conf=0.90)

  cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology source

In the paper

“Interestingly, soluble AβOs are known to enhance kinase activity triggering tau hyperphosphorylation at threonine 231 in primary neuronal cultures.16”

What the sources say

• Partly supported

  Results §§3.3 and 3.5 show that Aβ oligomers induced tau phosphorylation at Thr231 in primary hippocampal neuronal cultures and that Src-family kinase and PI3K inhibitors blocked it. The inhibitor results implicate kinase signaling, but the paper does not establish that the oligomers enhanced kinase activity; the Discussion presents pathway activation as a possibility. (LLM, conf=0.85)

  cites [16] De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging sourceExperimental — accuracy not yet measured

In the paper

“Conversely, in CI individuals, no CSF p-tau was found to be significantly superior, although CSF p-tau217 had numerically the highest AUC (0.99; 95% CI, 0.99-1.00).”

In the paper

“No significant differences were found between the CSF biomarkers when predicting tau PET positivity and all demonstrated comparable AUC values (AUC = 0.86-0.93, Figure 2d).”

In the paper

“All biomarkers had high accuracies (AUC > 0.96) in separating AD from non-AD and no biomarker was found to be statistically superior in this comparison.”

In the paper

“No marked difference was observed between CSF p-tau231 and CSF p-tau217, whilst CSF p-tau181 indicated weaker associations narrowed to reduced regions if compared to the other biomarkers (Figure 2e).”

In the paper

“Once more, correlations were inferior for CSF p-tau181 (r = 0.70, P < 0.001, Figure 3c) which were significantly different to other p-tau biomarkers (Pp-tau231 vs p-tau181< 0.001; Pp-tau217 vs p-tau181= 0.01).”

In the paper

“Similarly, CSF p-tau217 demonstrated the largest fold increase between CI Aβ+ and CI Aβ- (4.7-fold, P < 0.002; supplementary table 2). However, this was not significantly different to other CSF p-tau biomarkers.”

In the paper

“CSF p-tau217 was 6-fold higher in CI Aβ+ than in CU Aβ-, which was a significantly larger increase than other p-tau biomarkers (Pp-tau231=0.002; Pp-tau181=0.01; supplementary table 2).”

In the paper

“A stronger relationship between [18F]MK6240 and CSF p-tau231 and CSF p-tau217 (TCU>3.16; PCU<0.05) were found in CU participants, with significant associations confined to temporal regions corresponding to Braak stage regions I-IV (Figure 2g).”

In the paper

“CSF P-tau231 (AUC = 0.95; 95% CI, 0.92-0.98) and CSF p-tau217 (AUC = 0.95; 95% CI, 0.92-0.99) were significantly better predictors of Aβ PET status than CSF p-tau181 (AUC = 0.88; 95% CI, 0.81-0.94; both P < 0.01, Figure 3d).”

In the paper

“A noticeable decline in performance was observed for CSF p-tau181 when distinguishing MCI from non-AD (AUC = 0.83; 95% CI, 0.67-0.99) and MCI from CU (AUC = 0.81; 95% CI, 0.66-0.96) which was significantly different to p-tau231 and p-tau217 (P < 0.05 [DeLong's]).”

In the paper

“CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals.”

• Also stated in: § Funding · plain

  “p-tau217 exhibits larger fold-changes when symptomatic disease is apparent”

In the paper

“There was no association between sex and p-tau biomarkers when adjusting for age and diagnosis.”

In the paper

“In CU individuals, CSF p-tau231 (AUC = 0.91; 95% CI, 0.84-0.98) was significantly superior to CSF p-tau181 (AUC = 0.82; 95% CI, 0.71-0.93; P = 0.02) but not CSF p-tau217 (AUC = 0.90; 95% CI, 0.83-0.98; P=0.75).”

In the paper

“At the voxel level, CSF biomarkers were associated with higher [18F]MK6240 uptake in the inferior, medial and lateral temporal regions (Tall>3.14; Pall<0.05, Figure 2E), with associated areas overlapping between CSF biomarkers.”

In the paper

“This significantly outperformed CSF p-tau231 (P < 0.01[DeLong's]) but not CSF p-tau217 (P=0.13[DeLong's]).”

In the paper

“CSF p-tau231 (Figure 1a) and CSF p-tau217 (Figure 1b) were significantly increased in CU Aβ+ as compared to CI Aβ- but this was not observed for CSF p-tau181 (Figure 1c).”

In the paper

“Furthermore, we demonstrated that CSF p-tau231 displays the largest effect size in relation to Aβ deposition, both globally and regionally, and, amongst the biomarkers tested, is the first to achieve abnormal values.”

In the paper

“Contrarily, CSF biomarkers showed to become abnormal at different pathological stages, with CSF p-tau231 status being positive at approximately Centiloid 37, followed by CSF p-tau181 at Centiloid 47 and CSF p-tau217 at Centiloid 50.”

In the paper

“This was further substantiated by CSF p-tau231 having the largest beta values in relation to Aβ deposition and seemingly becoming abnormal before CSF p-tau217 and CSF p-tau181 when the pathophysiological progression was delineated by Aβ PET Centiloids.”

In the paper

“Using the ratio of Aβ42 to p-tau did not largely change our results but produced higher AUC's, which should be further investigated in larger cohort sizes or utilized if the optimal p-tau is not available, as highlighted in this study.”

In the paper

“In conclusion, this study documents the pronounced preclinical increases of CSF p-tau biomarkers but specifically highlights CSF p-tau231 which begins to associate with Aβ deposition before the threshold of Aβ PET positivity has occurred and strongly associates with known early Aβ accumulating regions in the DMN.”

In the paper

“Although CSF p-tau231 demonstrated numerically identical AUC's to CSF p-tau217 in the prediction of Aβ PET at CU stage of the AD continuum, only CSF p-tau231 and not CSF p-tau217 was significantly superior to CSF p-tau181.”

In the paper

“However, a numerical advantage was observed in CU participants (p-tau231/Aβ42, AUC = 0.96; 95% CI, 92-99%; p-tau217/Aβ42, AUC=95%; 95% CI, 91-99%).”

In the paper

“We demonstrate that CSF p-tau231 and CSF p-tau217 biomarkers have a similar relationship with [18F]MK6240 and [18F]AZD4694, being both better predictors of PET status in comparison with CSF p-tau181.”

In the paper

“In this study, we found that CSF p-tau231 and CSF p-tau217 associated with [18F]MK6240 to the same degree in the whole group and at both CI and CU stages, whereas CSF p-tau181 had weaker associations.”

In the paper

“We further performed a voxel-wise analysis in CU participants without prominent Aβ pathology (Aβ-) and demonstrated focal associations of CSF p-tau231 with emerging Aβ pathology in the medial orbitofrontal, precuneus and posterior/isthmus cingulate cortices which were stronger than what was observed for p-tau217 and absent for p-tau181.”

In the paper

“Voxel-based linear regression models evaluated the correlation between log transformed CSF values and PET biomarkers adjusting for age, sex, and diagnosis, when necessary.”

In the paper

“Both methods demonstrated intra and inter assay variation <8%.”

In the paper

“The mean age of the population was 62.77 years, with CI participants being older than CU (CU = 59.82; CI = 67.78; P < 0.001) owing to a proportion of the CU being < 30 years.”

In the paper

“APOE-ε4 carriers and males were also more common in the CI group.”

In the paper

“Linear regression models also tested the association between log-transformed CSF p-tau and other biomarkers always adjusting by age and gender.”

In the paper

“We demonstrate that CSF p-tau231 increases early in development of AD pathology”

• Also stated in: § Funding · hedged

  “Our novel finding suggests that CSF p-tau231 levels are raised earliest in preclinical AD.”

In the paper

“Random field theory46 was used to correct the resulting t parametric maps for multiple comparisons (one-sided).”

What the sources say

• ?Not checked — no full text of the sourcecites [46] Worsley, 2004, Unified univariate and multivariate random field theory, Neuroimage source

In the paper

“Neurofibrillary tangles (NFTs), primarily composed of abnormal hyperphosphorylated tau, are a key pathological hallmark of Alzheimer's disease (AD).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Scheltens, 2016, Alzheimer's disease, Lancet source

In the paper

“positivity was visually defined by two neurologists blinded to clinical diagnosis.”

In the paper

“As expected, the CI group had a lower MMSE scores, and higher Aβ PET and tau PET load as compared to the CU group (Table 1).”

In the paper

“No such changes were observed for other biomarkers demonstrating that CSF p-tau181 is not sensitive to early pathological changes but an accurate biomarker at late-stage disease.”

In the paper

“CSF p-tau biomarkers in this study are compared on two different platforms, with differing detection and capture antibody configurations: N-terminally derived CSF p-tau181 and CSF p-tau217 on the Simoa platform, Mid-terminal CSF p-tau231 by ELISA.”

In the paper

“CSF p-tau, regardless of phosphorylation site, has been considered as a biomarker of NFT pathology, while other studies propose CSF p-tau as a state marker for brain tau phosphorylation,62 yet the direct association between CSF p-tau and tau PET has been inconsistent.”

What the sources say

• ?Not checked — no full text of the sourcecites [62] Blennow, 2003, CSF markers for incipient Alzheimer's disease, Lancet Neurol source

In the paper

“In agreement to this, Janelidze et al. previously described that CSF p-tau217 had a consistently greater regional association to tau PET than CSF p-tau181 but CSF p-tau231 was not analyzed in this particular study.”

What the sources say

• ?Not matched

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

  cites Janelidze et al.

In the paper

“However, while it is presumed that p-tau secretion, and subsequent increase in CSF, occurs after globally aggregated Aβ, our data shows that CSF p-tau already changes with subtle Aβ pathology and therefore occurs considerably earlier than previously anticipated.”

In the paper

“In addition, the ADx253 antibody utilized in the p-tau231 ELISA was determined to simulate cis-selectivity however it cannot be determined the specific abundance of the toxic cis p-tau231 species in this assay format.”

In the paper

“Thus, CSF p-tau231 is a novel candidate for detecting early and emerging Aβ pathology in individuals for the recruitment into therapeutic trials, act as a target engagement biomarker to monitor the effect of Aβ therapeutics or supports the notion of therapeutically targeting tau epitopes in preclinical disease before tau aggregation can be visualized by tau PET.”

In the paper

“This finding further supports a model of active soluble tau release by cells into the CSF which is related to early Aβ deposition, likely induced by early Aβ seeds.”

In the paper

“Consequently, CSF p-tau231 could be a useful indicator of early Aβ deposition, which can have practical implications for highlighting early AD risk and enrich the enrollment of individuals in the pre-amyloid phase in clinical trials.”

In the paper

“As Aβ accumulates toward Aβ positivity, other p-tau epitopes (p-tau217 and p-tau181) then become abnormal with p-tau217 changing at quicker rate.”

In the paper

“This demonstrates that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and our data reveals that CSF p-tau231 is a stronger correlate to these early accumulating regions.”

In the paper

“Further to this, our main finding of early of pre-amyloid changes of p-tau231 is based on 83 CU Aβ- individuals and should be replicated in an independent cohort which is not enriched for AD with exclusion criteria's.”

In the paper

“Furthermore, the use of cross‐sectional Aβ PET Centiloids as a proxy of time in the disease was employed and while a gradual Aβ accumulation is observed though AD development, it is not certain that a greater Aβ PET SUVR is indicative of more advanced disease state.”

In the paper

“Thus, it cannot be ruled out that subtle changes in biomarkers performances are determined by platform differences or antibody superiority.”