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Cited by 93Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced MRI Techniques and Applications

In vivo imaging of tau pathology using multi-parametric quantitative MRI

Open access
Wells, J.A., O'Callaghan, J.M., Holmes, H.E., Powell, N.M., Johnson, R.A., Siow, B., Torrealdea, F., Ismail, O. +14 more·2015·NeuroImage
DOI 10.1016/j.neuroimage.2015.02.023PMC PMC4626540
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Abstract

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

AI snapshot

Written from the paper’s full text.

TL;DR

Multi-parametric quantitative MRI in the rTg4510 tauopathy mouse detects tau pathology across structural, diffusion, perfusion, CEST, and glucoCEST measures, with ASL and DTI showing changes in a low-NFT region before detectable atrophy. The authors propose this 5-tier imaging approach as a translatable platform for early tau-pathology detection and therapeutic evaluation.

Key findings

  • Structural MRI showed significant hippocampal atrophy in rTg4510 mice versus wild-type controls (normalized to total intracranial volume, p = 2 × 10−11, effect size = 5.5), and tensor-based morphometry detected bilateral atrophy in striatum, hippocampus, cortex, and forebrain plus ventricular dilation.
  • Quantitative MRI discriminated groups: increased radial diffusivity in corpus callosum (p = 1.6 × 10−8, effect size = 3.8), increased CBF in frontal cortex (p = 7.4 × 10−10, effect size = 3.8), decreased amide proton transfer in hippocampus (p = 1.16 × 10−10, effect size = 4.5), and increased glucoCEST in cortex (p = 0.01, effect size = 2.6). In corpus callosum, FA was reduced (0.32 ± 0.05 vs. 0.48 ± 0.07, p = 4.5 × 10−6) and MD was increased (9.4 ± 0.8 vs. 7.7 ± 0.4 × 10−4 mm2/s, p = 6.3 × 10−8), while axial diffusivity did not differ (p = 0.36).
  • Hippocampal volume correlated with NFT density (Pearson’s CC = 0.81, p = 0.01), but cortical volume did not (CC = 0.05, p = 0.58). Across ranked tau burden, CBF (Spearman’s CC = 0.78, p = 1.5 × 10−16), FA (CC = 0.48, p = 1 × 10−5), MD (CC = 0.57, p = 1.2 × 10−7), and CEST (negative, CC = 0.8, p = 4.7 × 10−14) correlated with tau density; mean NFT densities were 229 cells/mm2 in cortex, 83 cells/mm2 in hippocampus, and 2.3 cells/mm2 in thalamus.
  • In thalamus, a low-NFT region with no detectable atrophy, rTg4510 mice still showed increased CBF (p = 3 × 10−6) and MD (p = 0.04). Awake telemetry showed higher mean arterial pressure (average difference 17.4 mm Hg) and heart rate (average difference 142 bpm) in rTg4510 mice during the dark phase, but no significant differences under anaesthesia.

Methods

  • Two cohorts of rTg4510 and wild-type littermate controls were imaged at 8.5 and 9.5 months on a 9.4 T scanner. Cohort 1 (8.5 months) underwent ASL, DTI, and 3D structural imaging (N = 9 rTg4510, N = 17 wild-type); cohort 2 (9.5 months) underwent CEST (N = 10 rTg4510, N = 9 wild-type) and glucoCEST (N = 5 rTg4510, N = 5 wild-type, fasted 24 h).
  • Imaging included T2-weighted structural MRI with tensor-based morphometry, FAIR ASL for CBF, diffusion tensor imaging, CEST for amide proton transfer, and glucoCEST after intraperitoneal 1 g/kg glucose. Histology used PG-5 antibody against tau phosphorylated at serine 409 to quantify NFT density in cortex, hippocampus, and thalamus.
  • Group comparisons used t-tests; correlations used Pearson’s within regions and Spearman’s rank for ranked tau burden. TBM used FDR correction (q = 0.05) and a 20-voxel cluster threshold. A separate cohort underwent awake and anaesthetized telemetry for blood pressure and heart rate.

Limitations

  • The paper states that techniques were split across two separate cohorts of subtly different ages (8.5 and 9.5 months), and that the relatively late time point may restrict evidence for specificity of MRI parameters to abnormal tau because marked neurodegeneration may already have occurred.
  • The paper notes limited within-region correlations, likely due to narrow NFT-density distributions within each region; CEST changes may be non-specific because APT can be influenced by pH and T1; glucoCEST signal can arise from intravascular, extravascular–extracellular, or intracellular compartments; and thalamic changes may be secondary to severe forebrain pathology. DTI–histology correlation was not performed because no PG-5-positive staining was detected in corpus callosum.
  • Evident from the text: glucoCEST had small group sizes (n = 5 per group), the study was cross-sectional rather than longitudinal, and ROIs were manually drawn.

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

Integrity signals

Registry

Crossref · 10.1016/j.neuroimage.2015.02.023

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 47 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The failure of candidate drugs to show improvements in the human condition has caused a shift in interest to other therapeutic pathways.

    “The failure of these candidate drugs to date to show any improvements in the human condition has caused a shift in interest to other therapeutic pathways (Clavaguera et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Clavaguera et al., 2009 source

      The paper’s account of its findings describes transmission and spreading of tau pathology in mice, not outcomes of candidate drugs in humans. A search of our copy for failed drugs, clinical improvement, and a shift in therapeutic approaches found no passage addressing that claim. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
  • Premisecitation

    Structural MRI has established itself as a reliable biomarker in the clinical diagnosis of Alzheimer's disease.

    “Structural MRI has already established itself as a reliable biomarker in the clinical diagnosis of Alzheimer's disease (Dubois et al., 2007, Frisoni et al., 2010, Jack et al., 1997); characteristic grey matter reduction and ventricular enlargement can be visualised using standard T1-weighted sequences.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Dubois et al., 2007 source
    • cites Frisoni et al., 2010 source
    • cites Jack et al., 1997 source

      The Results report that hippocampal volume measurements distinguished patients with Alzheimer’s disease from controls, and the Discussion calls them a sensitive marker in very mild disease (pages not provided). But the Discussion describes the measurement as a potentially helpful adjunct to clinical diagnosis, not structural MRI generally as an already established, reliable clinical biomarker. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Expression of tau in the rTg4510 mouse is driven by a forebrain specific promoter (CaMKII).

    “This is to be expected as expression of tau is driven by a forebrain specific promoter (CaMKII) in the rTg4510 mouse (Ramsden et al., 2005).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ramsden et al., 2005 source
  • Interpretationcitation

    These findings are highly concordant with an earlier longitudinal study that applied DTI methods to investigate the white matter of the rTg4510 model.

    “These findings are highly concordant with an earlier longitudinal study that applied DTI methods to investigate the white matter of the rTg4510 model (Sahara et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Sahara et al., 2014 source

      The Results (section 3.2) report DTI measurements of white matter in rTg4510 mice at different ages. But the Methods (section 2.2) describe 29 mice allocated across three age groups, not repeated scans of the same mice; calling this a longitudinal study is unsupported. The citing authors’ assessment of concordance is their own framing. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Antemortem MRI has previously been found to correlate well with measures of cognitive deterioration and post-mortem Braak staging of Alzheimer's disease.

    “As well as revealing signs of atrophy, which can inform differential diagnosis of the disease, antemortem MRI has previously been found to correlate well with measures of cognitive deterioration and post-mortem Braak staging of the disease (Csernansky et al., 2004, Jack et al., 2002, Vemuri et al., 2008, Whitwell et al., 2008).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Csernansky et al., 2004
    • cites Jack et al., 2002 source
    • cites Vemuri et al., 2008 source
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    The rTg4510 mouse model specifically expresses tau in the forebrain without amyloid plaques.

    “A mouse model of tauopathy (rTg4510) has been developed that specifically expresses tau in the forebrain but without amyloid plaques”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Ramsden et al., 2005 source

      The Generation of transgenic mice section describes rTg4510 as a mutant human tau model and reports that transgenic tau expression was primarily restricted to the forebrain, especially the hippocampus and cortex (page not available). The passages searched for amyloid plaques do not report whether plaques were absent in these mice, so that part of the claim is not established by our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Santacruz et al., 2005 source

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

    Premisecitation

    APP mutant mice are the oldest and most widely studied models of AD.

    “Mice containing mutations in the amyloid precursor protein (APP) gene are the oldest and most widely studied models of AD”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hall and Robertson, 2012 source

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

    Premisecitation

    AD patients and subjects in prodromal disease stages present with regionally dependent hypo- and hyper-perfusion compared to healthy control subjects.

    “AD patients and subjects in prodromal disease stages present with regionally dependent hypo- and hyper-perfusion (Wolk and Detre, 2012) compared to healthy control subjects.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wolk and Detre, 2012 source

  • May combine two claims.

    Premisecitation

    Electron microscopy measures demonstrated the presence of tau inclusions in the white matter and subsequent micro-structural disorganisation relative to WT controls at later time points.

    “Electron microscopy measures were performed and demonstrated the presence of tau inclusions in the white matter and subsequent micro-structural disorganisation relative to WT controls at later time points (Sahara et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Sahara et al., 2014 source

  • May combine two claims.

    Premisecitation

    There is a paucity of studies that have applied ASL to mouse models of AD, although cortical hypo-perfusion has been reported in two amyloid models.

    “There is a paucity of studies that have applied ASL to mouse models of AD, although cortical hypo-perfusion has been reported in two amyloid models (Faure et al., 2011, Weidensteiner et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Faure et al., 2011 source
    • cites Weidensteiner et al., 2009 source

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

    Premisecitation

    Abnormal myelination patterns have been identified prior to appearance of NFTs and amyloid plaques in a mouse model exhibiting both pathologies.

    “Abnormal myelination patterns have been identified prior to appearance of NFTs and amyloid plaques in a mouse model exhibiting both pathologies (Desai et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Desai et al., 2009 source

  • May combine two claims.

    Premisecitation

    The rTg4510 mouse mimics features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus.

    “The rTg4510 mouse mimics the features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus (Ramsden et al., 2005, Santacruz et al., 2005).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Ramsden et al., 2005 source
    • cites Santacruz et al., 2005 source

  • May combine two claims.

    Premisecitation

    The MD measurements in grey matter regions are in good agreement with previous studies that have detected elevated values in the brains of AD patients and in mouse models exhibiting amyloid pathology at late stages of progression.

    “The MD measurements in grey matter regions are in good agreement with previous studies that have detected elevated values in the brains of AD patients (Fellgiebel et al., 2004, Kantarci et al., 2001, Rose et al., 2008) and in mouse models exhibiting amyloid pathology at late stages of progression (Sun et al., 2005).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Fellgiebel et al., 2004 source
    • cites Kantarci et al., 2001 source
    • cites Rose et al., 2008 source

  • May combine two claims.

    Premisecitation

    The pattern of brain atrophy is closely related to regional NFT accumulation found in Alzheimer's disease patients and is quite different from the pattern of amyloid plaques.

    “The pattern of brain atrophy is closely related to regional NFT accumulation found in AD patients (and quite different to the pattern of amyloid plaques) (Braak and Braak, 1991, McDonald et al., 2009), and thus atrophy remains a valuable biomarker in the evaluation of tau based therapeutics.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Braak and Braak, 1991 source
    • cites McDonald et al., 2009 source

      The Abstract and Discussion describe regional patterns of atrophy in MCI and early AD, but do not compare those patterns with neurofibrillary tangles or amyloid plaques. Searches for NFT accumulation and amyloid plaques found no passage in our copy addressing the claimed relationship. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

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

    Premisecitation

    There is post-mortem evidence in AD for regional spread of tau pathology, and more recent neuroimaging studies in human AD suggest epicentres or nodes that may link to network dysfunction.

    “There is post-mortem evidence in AD for this regional spread (Zhou Gennatas et al., 2012) and more recent neuroimaging studies in human AD suggest “epicentres” (Zhou et al., 2012) or “nodes” (Raj et al., 2012) that may link to network dysfunction.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Zhou Gennatas et al., 2012

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

    • cites Zhou et al., 2012 source

      The Discussion (‘Exploring the target networks: epicenters and early disease spread’; page unavailable) proposes an angular-gyrus epicenter in AD and links healthy-brain connectivity to the pattern of neurodegeneration, supporting the neuroimaging portion of the claim. It also suspects that its AD findings largely reflect tau pathology, but does not present post-mortem evidence for regional spread of tau pathology in AD; that portion is not supported by this paper’s text. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Raj et al., 2012 source

  • May combine two claims.

    Interpretationcitation

    Differences in APT may also be influenced by pH and longitudinal relaxation time (T1), meaning that as a biomarker, CEST distinguishes normal controls from rTg4510 mice but does so in a non-specific manner.

    “However the differences in APT may also be influenced by pH and the longitudinal relaxation time (T1), which may change due to cell death, for example (van Zijl and Yadav, 2011), meaning that as a biomarker, CEST distinguishes normal controls from rTg4510 mice but does so in a non-specific manner.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites van Zijl and Yadav, 2011 source

      The paper’s ‘In vivo CEST imaging and translation to humans’ section says pH reduction can reduce APT/CEST contrast, and ‘Signal and Parameter Quantification’ says water T1 must be known to quantify a CEST parameter. These passages support pH and T1 as influences, but the paper does not link a T1 change to cell death. The rTg4510 comparison is the citing authors’ conclusion, not a finding attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Tau aggregates can transfer and propagate/spread within synaptic circuits.

    “This may be important as we know that tau aggregates can transfer and propagate/spread within synaptic circuits (Clavaguera et al., 2009, de Calignon et al., 2012).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Clavaguera et al., 2009 source

      The paper reports experimental transmission of tau pathology and its spread to anatomically connected brain regions after injection of tau-containing extract (Abstract; page unavailable). It does not establish that tau aggregates transfer through synapses or propagate specifically within synaptic circuits; the mechanism of cell-to-cell spread is presented as a question for further investigation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites de Calignon et al., 2012 source

      The Discussion reports tau transfer to synaptically connected neurons in rTgTauEC mice, supporting circuit-based spread. But it explicitly asks which species transfers the aggregated state and whether that species is itself aggregated; the paper does not establish that tau aggregates themselves transfer. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Increased glucoCEST was recorded in the cortex of rTg4510 mice, with no significant differences detected in other regions.

    “Increased glucoCEST was recorded in the cortex although no significant differences were detected in other regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TBM detected extensive bilateral changes in the rTg4510 brain, including substantial atrophy of the striatum and dilation of the lateral, third and fourth ventricles.

    “Extensive bilateral changes throughout the transgenic brain relative to the group average were observed, including substantial atrophy of the striatum and dilation of the lateral, third and fourth ventricles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TBM detected significant bilateral hippocampal atrophy and local contraction within the cortex and forebrain of the rTg4510 population.

    “TBM also detected significant bilateral hippocampal atrophy and local contraction within the cortex and forebrain of the transgenic population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rTg4510 mice had higher mean arterial pressure and heart rate compared to wild type mice during the active 12-hour dark phase of the 24-hour conscious study interval.

    “rTg4510 mice had higher mean arterial pressure (MAP) and heart rate compared to the wild type mice during the active 12-hour dark phase of the 24-hour conscious study interval.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The average difference in heart rate between rTg4510 and wild type groups was 142 bpm, with a maximum difference at the 6th hour of 183 ± 27 bpm and a minimum difference at the 12th hour of 68 ± 24 bpm.

    “The average difference in the heart rate between groups was 142 bpm, with a maximum difference at the 6th hour of 183 bpm ± 27 and a minimum difference at the 12th hour of 68 bpm ± 24.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The average difference in MAP between rTg4510 and wild type groups was 17.4 mm Hg, with a maximum difference at the 9th hour of 24.1 ± 5.5 mm Hg and a minimum difference at the 12th hour of 9.0 ± 6.5 mm Hg.

    “The average difference in MAP between groups was 17.4 mm Hg, with a maximum difference at the 9th hour of 24.1 mm Hg ± 5.5 and a minimum difference at the 12th hour of 9.0 mm Hg ± 6.5.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In this work, increased CBF was observed in rTg4510 mice, which correlated with ranking of tau burden across different brain regions.

    “In this work we have observed increased CBF in the rTg4510 mice, which correlated with ranking of tau burden across different brain regions (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FA was increased significantly in the cortex and hippocampus in the transgenic mice and there was no significant difference in the thalamus.

    “where the FA was increased significantly in the cortex and hippocampus in the transgenic mice and there is no significant difference in the thalamus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using TBM, local volume reductions were detected in the cortex, hippocampus, caudate putamen (striatum) and olfactory bulbs as well as ventricular expansion in rTg4510 mice.

    “Using TBM, we were able to extend these observations and additionally detect local volume reductions in the cortex, hippocampus, caudate putamen (striatum) and olfactory bulbs as well as ventricular expansion (Fig. 1A–F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The thalamus of rTg4510 mice was found to have relatively low NFT density (mean = 2.3 cells/mm2) with no detectable atrophy based on TBM.

    “The thalamus of the rTg4510 mice was found to have relatively low NFT density (mean = 2.3 cells/mm2) with no detectable atrophy (based on TBM)”
    Quote in the paperSubstantial claim

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

    Premisecitation

    NFTs are implicated in several other neurodegenerative diseases in the absence of amyloid-beta.

    “In the absence of amyloid-beta, NFTs are also implicated in several other neurodegenerative diseases (frontotemporal dementia with parkinsonism, progressive supranuclear palsey, corticobasal degeneration), further supporting the role of tau in the dementing process (Lee et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al., 2001 source

  • May combine two claims.

    Premisecitation

    Tau aggregates forming neurofibrillary tangles (NFTs) are a major hallmark of Alzheimer's disease and correlate with clinical disease progression.

    “aggregates of hyperphosphorlylated tau forming neurofibrillary tangles (NFTs) are a major hallmark of AD and correlate with clinical disease progression (Braak and Braak, 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Braak and Braak, 1991 source

  • May combine two claims.

    Interpretationown data

    ASL and DTI are valuable for identification of tau-driven pathological processes prior to marked atrophy, suggesting utility as biomarkers for early assessment of novel tau therapeutics.

    “This finding demonstrates the value of ASL and DTI for the identification of tau-driven pathological processes prior to marked atrophy, suggesting their utility as biomarkers for the early assessment of novel tau therapeutics.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    This is the first application of ASL and CEST to the rTg4510 model and the first report of glucoCEST to investigate neurodegenerative disease.

    “This is the first application of ASL and CEST to the rTg4510 model as well as the first report of glucoCEST to investigate neurodegenerative disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    A monotonic relationship exists between measures of CBF, APT, MD, FA and NFT density within a degree of tau burden, which dissociates between regions of high tau burden (cortex and hippocampus) in 8.5 month rTg4510 mice.

    “This finding suggests a monotonic relationship exists between measures of CBF, APT, MD, FA and NFT density within a degree of tau burden which dissociates between regions of “high” tau burden (the cortex and hippocampus) in the 8.5 month rTg4510 mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ranked tau burden (0, 1, 2) accurately represents tau pathology severity across brain regions.

  • May combine two claims.

    Premisecitation

    Behavioural and histological studies of the rTg4510 mouse have demonstrated cognitive deficits in learning and motor tasks and marked atrophy of brain regions known to be selectively vulnerable to AD such as the hippocampus and frontal cortex.

    “Behavioural and histological studies of the rTg4510 mouse have demonstrated cognitive deficits in learning and motor tasks and marked atrophy of brain regions known to be selectively vulnerable to AD such as the hippocampus and frontal cortex (Santacruz et al., 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Santacruz et al., 2005 source

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

    Study design and conductnone given

    A limitation of this study is the division of the applied techniques into two separate cohorts of rTg4510 and control mice of subtly different ages (8.5 and 9.5 months).

    “It should be noted that a limitation of this study is the division of the applied techniques into two separate cohorts of rTg4510 and control mice of subtlety different ages (8.5 and 9.5 months).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The effects of amyloid plaques have been investigated in previous studies where differences in DTI parameters have been observed at late time points after the appearance of amyloid plaques.

    “The effects of amyloid plaques, the other hallmark pathology of AD, have been investigated in previous studies (Song et al., 2004, Sun et al., 2005) where differences in DTI parameters have been observed at late time points after the appearance of amyloid plaques.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Song et al., 2004 source
    • cites Sun et al., 2005 source

  • May combine two claims.

    Interpretationown data

    The similarity of blood pressure measurements in anaesthetised rTg4510 and wildtype animals indicates that systemic differences in BP are not responsible for the elevated CBF in rTg4510 animals, and that the observed hyper-perfusion is brain specific.

    “The similarity of the blood pressure measurements in the anaesthetised rTg4510 and wildtype animals indicates that systemic differences in BP are not responsible for the elevated CBF in the rTg4510 animals, and that the observed hyper-perfusion is brain specific.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Magnetisation transfer ratio has been studied in clinical Alzheimer's disease.

    “Magnetisation transfer ratio has been studied in clinical Alzheimer's disease (Hentschel et al., 2004, van Es et al., 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hentschel et al., 2004 source
    • cites van Es et al., 2006 source

  • May combine two claims.

    Interpretationown data

    These morphometric changes coincide with NFT pathology, thereby supporting the role of tau in neurodegeneration.

    “These morphometric changes coincide with NFT pathology, thereby supporting the role of tau in neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    CEST MRI differs from magnetization transfer studies by probing the chemical exchange in mobile compounds rather than semisolids.

    “CEST MRI differs from magnetization transfer studies by probing the chemical exchange in mobile compounds rather than semisolids (van Jijl and Yadav, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites van Jijl and Yadav, 2001

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

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

    Premisecitation

    Previously published work has reported structural changes in rTg4510 mice in the hippocampus and cerebral cortex, as well as enlargement of the ventricles using in vivo MRI.

    “Previously published work has reported structural changes in rTg4510 mice in the hippocampus and cerebral cortex, as well as enlargement of the ventricles using in vivo MRI (Yang et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., 2011 source

  • May combine two claims.

    Interpretationreasoning

    The increased cortical glucoCEST signal measured in rTg4510s could be caused by increased accumulation of glucose in the tissue due to a reduction in glucose metabolism alongside an increased delivery due to the elevated CBF to the cortical regions.

    “The increased cortical glucoCEST signal that we measured in the rTg4510s could therefore be caused by increased accumulation of glucose in the tissue due to a reduction in glucose metabolism alongside an increased delivery due to the elevated CBF to the cortical regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Microstructural and haemodynamic changes that occur without gross neuronal loss can be detected in the thalamus with MRI, and this highlights the value of multi-parametric measures in the same subject for sensitive detection of tau pathology.

    “This finding suggests that microstructural and haemodynamic changes that occur without gross neuronal loss can be detected in this brain region with MRI and highlights the value of multi-parametric measures in the same subject for sensitive detection of tau pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The technique's ability to clearly distinguish tau pathology is the first application to neuro-degeneration and provides further insight into the metabolic processes of tau pathology.

    “The technique's ability to clearly distinguish tau pathology is the first application to neuro-degeneration and provides further insight into the metabolic processes of the tau pathology.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The reduction in APT in the rTg4510 animals may indicate a break down in normal chemical exchange caused by tau pathology.

    “The reduction in APT in the rTg4510 animals may indicate a break down in normal chemical exchange caused by tau pathology.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    The multi-parametric MRI techniques used in this study are translatable to human AD.

    “five translatable MRI techniques”
    “providing evidence that these data may inform the development of a multi-parametric imaging biomarker for early detection of tau pathology in the clinic.”

  • The paper relies on this without support.

    Most APP mice form plaques but do not have tangle pathology or evidence of robust neurodegeneration.

    “while most APP mice form plaques they do not have tangle pathology or evidence of robust neurodegeneration.”

  • The paper relies on this without support.

    PG-5 immunoreactivity density is a valid measure of NFT density/tau burden.

    “the number density of PG5 immunoreactivity was quantified”
    “estimate the density of PG-5 positive NFTs”

  • The paper relies on this without support.

    The ranked tau burden (0, 1, 2) accurately represents tau pathology severity across brain regions.

    “rTg4510 brain regions were ranked as 0 (wildtype control mice), low (thalamus of rTg4510 mice) and high (cortex and hippocampus of rTg4510 mice) tau burden.”

  • The paper relies on this without support.

    The observed differences between rTg4510 and WT mice are caused by tau pathology rather than other differences between the transgenic and control mice.

    “Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion.”

  • The paper relies on this without support.

    DTI is a sensitive measure of local tissue inflammation and cellular integrity.

    “DTI) (a sensitive measure of local tissue inflammation and cellular integrity)”

  • The paper relies on this without support.

    ASL and glucoCEST measures of perfusion and glucose uptake reflect changes in cerebral metabolism, vasculature and neuronal excitability.

    “to measure perfusion and glucose delivery and uptake to infer changes in cerebral metabolism, vasculature and neuronal excitability”

  • The paper relies on this without support.

    The rTg4510 mouse model's tau pathology is representative enough of human Alzheimer's disease tau pathology to translate the imaging findings to clinical AD.

    “The rTg4510 mouse mimics the features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus (Ramsden et al., 2005, Santacruz et al., 2005).”
8 of 8

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?

  • Effects of tauopathy on DTI metrics in grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies.

    “Effects of tauopathy on DTI metrics in the grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies [17,18,23,25,28,29,33,38,57].”

    From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [29]

    The Discussion (page not provided) links white-matter DTI changes in tauopathy-model mice to possible reduced myelination and describes grey-matter DTI changes as possible cytoarchitectural disruption. It does not identify axonal damage or gliosis as contributors to those DTI changes, so it supports only part of the proposed list of mechanisms. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Histological studies have demonstrated deposition of NFTs pathology, in particular in the cortex and hippocampus, and marked atrophy of these areas.

    “Histological studies have demonstrated deposition of NFTs pathology, in particular, in the cortex (CRX) and hippocampus and marked atrophy of these areas [27][28][29][30][31][32].”

    From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [29]

  • Several studies have suggested that oligomeric tau in soluble forms may be the most potent neurotoxic form.

    “Although tau aggregates are hallmarks of AD, several studies have suggested that oligomeric tau in soluble forms may be the most potent neurotoxic form 68–73.”

    From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [68]

    The Introduction describes tau aggregates and neurofibrillary tangles as hallmarks of Alzheimer’s disease, but does not compare their toxicity with soluble tau. Searches for soluble oligomeric tau and tau toxicity found no passage in our copy addressing whether soluble oligomers may be the most potent neurotoxic form. The indexed passages have no page numbers. (LLM, conf=0.73)

    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.

  • Hippocampal volume-NFT correlation has opposite signs

    Major

    The Results report a positive correlation of 0.81 between hippocampal volume and NFT density, but the Discussion calls the measured correlation negative.

  • Radial-diffusivity p-value differs between Results sections

    Minor

    The same corpus-callosum radial-diffusivity comparison is reported with two different p-values, both printed to two significant figures.

  • CEST correlation is described as negative but reported as positive

    Minor

    A Spearman correlation coefficient of 0.8 is positive, whereas the same result is described as a negative relationship.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hentschel, 2004, Does magnetization transfer ratio (MTR) contribute to the diagnosis and differential diagnosis of the dementias?, Röfo, 176, 1743

Cited by

Sorted by citations

Related

Authors
Wells, J. A., O'Callaghan, J. M., Holmes, H. E., Powell, N. M., Johnson, R. A., Siow, B., Torrealdea, F., Ismail, O., Walker-Samuel, S., Golay, X., Rega, M., Richardson, S., Modat, M., Cardoso, M. J., Ourselin, S., Schwarz, A. J., Ahmed, Z., Murray, T. K., O'Neill, M. J., Collins, E. C., Colgan, N., & Lythgoe, M. F.
Affiliations
  • University College London (GB)
  • Eli Lilly (United Kingdom) (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Eli Lilly (United States) (US)
Corresponding author
Wells, J.A.
ORCID
Venue
NeuroImage
Publisher
Elsevier BV
Published
2015-05
Volume
111
Pages
369-378
ISSN
1053-8119 (ISSN-L)
DOI
10.1016/j.neuroimage.2015.02.023
PMC
PMC4626540
OpenAlex
W1973685603
Semantic Scholar
01bdef49e66a1072d9984d79fed7be9deff75b88
Cited by
93
References
65
Citations by year
2026: 2 · 2025: 10 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 6 · 2020: 7 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 5 · 2015: 5
FWCI
7.30
Type
journal article
Language
en
Open access
Licence
Locations
  • NeuroImage (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Neuropathology Group
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
Keywords
tau pathology, Alzheimer's disease, neurofibrillary tangles, multiparametric MRI, diffusion tensor imaging, arterial spin labeling, chemical exchange saturation transfer, amide proton transfer, white matter integrity, cerebral hyperperfusion, gray matter atrophy
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Female, Magnetic Resonance Imaging, Mice, Transgenic, Biomarkers, tau Proteins, Tauopathies, Mice

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 2026-10-24.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-24.

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.

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