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Cited by 28Advanced Neuroimaging Techniques and ApplicationsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy.

Open access
Massalimova, Aidana, Ni, Ruiqing, Nitsch, Roger M., Reisert, Marco, von Elverfeldt, Dominik, Klohs, Jan·2020·Neurodegenerative Diseases
DOI 10.1159/000515754

Published version of a preprint

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Abstract

INTRODUCTION: Increased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high-resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months of age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data. METHODS: Hemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) maps. VBA on the entire brain was performed using SPM8 and the SPM Mouse toolbox. Initially, all DTI maps were coregistered with the Allen mouse brain atlas to bring them to one common coordinate space. In VBA, coregistered DTI maps were normalized and smoothed in order to perform two-sample and unpaired t tests with false discovery rate correction to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, and hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions of interests were computed with coregistered DTI maps and labels in Allen mouse brain atlas. Afterwards, a Kruskal-Wallis one-way ANOVA on ranks with a Tukey post hoc test was executed on the estimated average values. RESULTS: With VBA, we found pronounced and brain-wide spread changes when comparing homozygous, P301L mice with non-transgenic littermates, which were not seen when comparing hemizygous P301L with non-transgenic animals. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD, and AD were increased in homozygotes compared to hemizygotes and non-transgenic littermates. DISCUSSION/CONCLUSION: High-resolution ex vivo DTI demonstrated brain-wide microstructural and gene-dose-dependent changes in the P301L mouse model of human tauopathy. The DTI analysis pipeline may serve for the phenotyping of models of tauopathy and other brain diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Ex vivo high-resolution DTI in 8.5-month-old P301L tauopathy mice revealed brain-wide, gene-dose-dependent microstructural changes: homozygous P301L mice differed strongly from non-transgenic littermates, whereas hemizygous P301L mice did not show comparable voxel-wise differences. The findings support DTI as a phenotyping tool for tauopathy models, with decreased FA and increased MD, RD, and AD in homozygotes.

Key findings

  • VBA found pronounced brain-wide changes in white and grey matter when comparing homozygous P301L mice with non-transgenic littermates, but no differences when comparing hemizygous P301L mice with non-transgenic littermates.
  • ABA corroborated VBA: FA was decreased in most brain regions, while MD, RD, and AD were increased in homozygous P301L mice compared with hemizygous and non-transgenic littermates.
  • In the corpus callosum, Table 1 reports FA of 0.58 ± 0.05 in non-transgenic, 0.58 ± 0.05 in hemizygous, and 0.51 ± 0.02 in homozygous P301L mice; MD was 0.14 ± 0.02, 0.15 ± 0.03, and 0.18 ± 0.01, respectively.
  • The authors conclude that DTI changes are gene-dose dependent, with the stronger tau transgene expression in homozygous P301L mice producing the phenotype.

Methods

  • Hemizygous P301L mice (n = 8; 5 females/3 males), homozygous P301L mice (n = 8; 5 females/3 males), and age-matched non-transgenic littermates (n = 8; 2 females/6 males) were imaged at 8.5 months of age.
  • Ex vivo DTI was acquired with a 3D multishot echo-planar imaging sequence at 100 × 100 × 100 μm nominal voxel resolution, b-value 4,000 s/mm² along 60 diffusion encoding directions, total acquisition time 9 h 45 min.
  • VBA used SPM8 and the SPM Mouse toolbox with unpaired two-sample t tests and clusterwise FDR correction (p < 0.001); ABA used the Allen mouse brain atlas and selected ROIs (AC, CC, CPD, CRX, HPR, SUB, TH), with Kruskal-Wallis one-way ANOVA on ranks and Tukey post hoc tests.

Limitations

  • The paper states that ex vivo DTI requires formaldehyde fixation, which alters macroscopic and microscopic tissue properties, including diffusion magnitude and volume changes, although directionality measures are less affected and PBS storage partially restores diffusivity.
  • The paper notes VBA limitations: smoothing is challenging in DTI due to thin white matter tracts and FA heterogeneity, statistical power is poor due to high noise, and VBA does not inform the direction of changes; ABA can fail when regions fall outside predefined atlas boundaries.
  • The paper states that interpretation of diffusion tensor changes awaits histological determination, and future longitudinal in vivo studies are needed; it also speculates that larger group sizes or older animals might reveal differences between hemizygous P301L and non-transgenic mice. Evident from the text: the study is cross-sectional, and the reported text statement that FA was reduced in CPD and CRX in hemizygotes versus non-transgenic controls is not consistently reflected in Table 1, where CPD FA is higher in hemizygotes (0.61 ± 0.07 vs 0.55 ± 0.05) and CRX FA is similar (0.29 ± 0.02 vs 0.28 ± 0.02).

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

Integrity signals

Registry

Crossref · 10.1159/000515754

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 56 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Previous DTI studies assessing microstructural changes in rTg4510 mice produced conflicting results.

    “Previous DTI studies assessing microstructural changes in rTg4510 mice, which express transgenic tau P301L mutations driven by a Ca 2+ / calmodulin kinase II promoter system [30,31] in the white and grey matter produced conflicting results [33][34][35][36].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [33] source
    • cites [34] source

      The Introduction describes inconsistent findings about volume changes between in vivo and ex vivo imaging, not conflicting DTI findings in rTg4510 mice. The Experimental Data section identifies the mouse model, but neither it nor the additional passages retrieved for DTI and microstructural changes addresses the attributed claim. No page numbers were provided in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [35] source
  • Premisecitation

    Long data acquisitions possible in ex vivo DTI allow high spatial resolution without image corruption due to motion or breathing that are common in in vivo DTI.

    “We leveraged the ability of long data acquisitions that are possible in ex vivo DTI to achieve a high spatial resolution, without suffering from image corruption due to motion or breathing that are common in in vivo DTI [12,13].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] source

      The Methods (MRH protocols; page not provided) report a 95.3-hour diffusion MRI acquisition at 25 μm isotropic resolution, supporting the long-acquisition, high-resolution portion of the claim. The passages do not address whether ex vivo imaging avoids corruption from motion or breathing, or whether those artifacts are common in in vivo DTI. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [13] source

      The Diffusion-Weighted Image Acquisition section says subject motion can corrupt diffusion-weighted images, and Protocol Considerations discusses scan-time and spatial-resolution constraints. But the paper does not state that ex vivo DTI permits long acquisitions without motion or breathing artifacts, so it supports only the general imaging considerations, not the ex vivo comparison. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The observed pattern of decreased FA and increased MD, RD, and AD in P301L mice is in good agreement with DTI changes observed in human tauopathies such as progressive supranuclear palsy, frontotemporal dementia, mild cognitive impairment, and Alzheimer's disease.

    “In this regard, the observed pattern of decreased FA and increased MD, RD, and AD values in P301L mice in the current study are in good agreement with DTI changes observed in human tauopathies such as progressive supranuclear palsy [21], frontotemporal dementia [22], mild cognitive impairment [24], and Alzheimer`s disease [18,25].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [21] source

      The Results (section 3.3) and Discussion (section 4) report higher MD and lower FA in specific white-matter regions with more advanced Alzheimer’s pathology, supporting the Alzheimer’s disease comparison. The paper does not report increased RD or AD, so it does not support the full four-measure pattern attributed to the human findings. The other named conditions have separate citations in the citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] source
    • cites [24] source
  • Findingown data

    Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA.

    “Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In ABA, AD values were significantly increased in the AC, CC, CPD, CRX, HPR, and TH in homozygous P301L mice compared to non-transgenic littermates.

    “AD values were significantly increased in the AC, CC, CPD, CRX, HPR, and TH in homozygous P301L mice compared to non-transgenic littermates.”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 30
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    For ROI analysis, selected areas are manually drawn, which is more time consuming, requires a priori anatomical localization, and is prone to bias.

    “For ROI analysis, selected areas are manually drawn, which is more time consuming, requires a priori anatomical localization, and is prone to bias [48].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [48] source

      The Discussion describes computation time for diffusion-MRI model fitting, not time spent drawing ROIs. Searches for manual ROI delineation, anatomical localization, and selection bias found no passage addressing those claims in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    VBA has been widely used in structural MRI as an unbiased approach to assess morphological changes of tissue.

    “VBA has been widely used in structural MRI as an unbiased approach to assess morphological changes of tissue [43,50].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [43] source

      The Discussion (page unavailable) says voxel-based analysis is widely used for whole-brain analysis without an a priori hypothesis, supporting the claim’s ‘widely used’ and ‘unbiased’ characterization. But it discusses DTI-derived measures and white-matter abnormalities, not the use of VBA in structural MRI to assess tissue morphology. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [50]

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

  • May combine two claims.

    Premisecitation

    Ex vivo DTI requires chemical fixation with formaldehyde to preserve tissue, and the procedure alters the macroscopic and microscopic properties of the tissue.

    “Nevertheless, ex vivo DTI requires chemical fixation with formaldehyde to preserve the tissue and the procedure alters the macroscopic and microscopic properties of the tissue.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] source

      The Methods section (1.2.2; page unavailable) describes DTI scans of participants, not ex vivo tissue preparation. Searches for formaldehyde fixation and ex vivo DTI found no passage addressing whether fixation is required or alters tissue properties. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Fixation alters the magnitude of water diffusion in tissue, but measures of the directionality of diffusion are less affected.

    “Fixation does alter the magnitude of water diffusion in the tissue, but measures of the directionality of diffusion are less affected [44][45][46].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [44] source
    • cites [45] source

      The Discussion says fixation techniques can cause tissue shrinkage, but does not discuss their effects on water-diffusion magnitude or directionality. Searches for fixation and diffusion measures found no passage addressing that comparison. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [46] source

      The section on chronic cerebral hypoperfusion describes arterial water as a diffusible tracer, and the imaging-techniques table mentions diffusion tensor imaging, but neither addresses tissue fixation. Searches for fixation, diffusivity, and anisotropy found no passage comparing fixation’s effects on diffusion magnitude and directionality. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Behavioural analysis revealed cognitive deficits in learning and motor tasks.

    “Behavioural analysis revealed cognitive deficits in learning and motor tasks [30,31].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [30] source

      The Materials and methods (Magnetic resonance imaging; page unavailable) describe MRI scans and subsequent histologic evaluation, not behavioural tests. Searches for behavioural testing and learning or motor tasks found no passage reporting deficits in those tasks. The Introduction mentions cognitive status generally, but does not establish the claimed behavioural result. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [31] source

      The Introduction and Discussion report impaired memory in P301L mice on hippocampus- and amygdala-dependent tasks, supporting the learning-related part of the claim. The paper reports this from earlier studies rather than presenting its own behavioural analysis, and our copy does not report deficits on motor tasks. Page numbers are unavailable in the indexed copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim5 of 9 sources checked
    • cites [17] source

      The Discussion (page unavailable) says the basis of DTI changes is uncertain and identifies possible contributions from axonal and myelin degeneration, oligodendrocyte loss, reactive astrocytosis, and reduced neuropil density in Alzheimer’s disease. The Introduction also describes neuronal loss in Alzheimer’s disease. However, this paper studies DTI changes in white matter; it does not establish the claimed effects on grey-matter DTI metrics or across tauopathies generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] source

      The supplied passages and the passages retrieved under the DOI are labeled as a different paper, “Pathophysiology of the behavioral variant of frontotemporal lobar degeneration: A study combining MRI and FDG-PET”; its References section lists Zhang et al. rather than providing that paper’s text. Searches for axonal damage, myelin injury, gliosis, and DTI metrics returned no passage from Zhang et al. that can verify the claim. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [23] source

      The Introduction describes neurodegeneration and tau inclusions in neurons and sometimes glia; “Impacts of Tau Mutations on Aggregation and Seeding” discusses impaired axonal transport as a possible mechanism. Our copy does not link these findings to grey- or white-matter DTI metrics, or report myelin injury or gliosis. Glial tau inclusions do not themselves establish gliosis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] source
    • cites [28] source

      The paper’s introductory text describes disruption of the axonal framework in tau disease, and its Abstract and Discussion report neuronal loss in tauopathy mouse models. It does not assess DTI metrics or myelin injury. The Discussion mentions astrogliosis as a possible source of PET-tracer signal, not as a demonstrated contributor to the claimed DTI effects. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [29] source

      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
    • cites [33] source
    • cites [38] source
    • cites [57]

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

  • May combine two claims.

    Premisecitation

    DTI shows sensitivity to axon and myelin pathology, where breakdown of white matter integrity results in measurable differences in diffusion of water molecules.

    “DTI shows sensitivity to axon and myelin pathology, where breakdown of white matter integrity results in measurable differences in diffusion of water molecules [15,16].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] source

      The Abstract (page unavailable) reports reduced fractional anisotropy measured by DTI as evidence of altered white matter structure in mice. The Discussion (page unavailable) relates FA changes to myelination, but the paper does not establish sensitivity to both axon and myelin pathology or explain the changes as differences in water-molecule diffusion. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [16] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Genetic studies show that the development of neurodegenerative tauopathies is associated with missense mutations in the microtubule-associated tau protein (MAPT).

    “Genetic studies show that the development of neurodegenerative tauopathies is associated with missense mutations in the microtubule-associated tau protein (MAPT) [26].”
    Quote in the paperSubstantial claim1 of 1 sources checked

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

    Premisecitation

    The occurrence of NFTs correlates well with spatial patterns of neuronal loss and is related to the degree of cognitive deficits.

    “The occurrence of NFTs correlates well with spatial patterns of neuronal loss and is related to the degree of cognitive deficits [3,4].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source

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

    Premisecitation

    The presence of NFTs in the brain triggers a complex cascade of biochemical and cellular processes that result in neurodegeneration and neuronal loss.

    “The presence of NFTs in the brain triggers a complex cascade of biochemical and cellular processes that result in neurodegeneration and neuronal loss [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] source

      The Alzheimer’s Disease section says that a neuron bearing a mature NFT dies. The paper also describes biochemical and cellular processes associated with neuronal death across neurodegenerative diseases, but it does not say that NFTs trigger that cascade. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    White matter changes such as white matter atrophy and the occurrence of white matter hyperintensities have been reported.

    “In addition, white matter changes such as white matter atrophy and the occurrence of white matter hyperintensities have been reported [9].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] source

      The Results section ('Cerebral vessel pathology and vascular lesions in FTLD-tau and AD'; page unavailable) reports white matter lesions and, in Pick’s disease, white matter degeneration and demyelination. It does not report white matter atrophy or white matter hyperintensities specifically; searches for those terms found no supporting passage in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Diffusion-weighted imaging probes the directional diffusivity of water molecules and can yield information about the microstructural properties of brain tissue.

    “Diffusion-weighted imaging is a MRI technique that probes the directional diffusivity of water molecules and can, thus, yield information about the microstructural properties of brain tissue [11][12][13].”
    Quote in the paperSubstantial claim3 of 3 sources checked

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

    Premisecitation

    A b-value of 4,000 s/mm2 is recommended for ex vivo DTI.

    “We used a b-value of 4,000 s/mm 2 , as recommended for ex vivo DTI [47].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [47] source

      The Technical Considerations section explains how DTI measures diffusivity, but gives no recommended b-value for ex vivo imaging. Searches of our untruncated copy for “4,000,” “4000,” “b-value,” and “ex vivo” found no passage addressing the claimed recommendation. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim3 of 3 sources checked

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

    Premisecitation

    Structural MRI studies have shown that NFT deposition is associated with grey matter atrophy resulting from neurodegeneration, and that different tauopathies display distinctive regional patterns of grey matter atrophy.

    “Structural MRI studies have shown that NFT deposition is associated with grey matter atrophy that results from neurodegeneration and that different tauopathies display distinctive regional patterns of grey matter atrophy [5][6][7][8].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [5] source
    • cites [6] source

      The Results and Discussion (page numbers unavailable) report MRI atrophy patterns alongside neuropathology: MAPT-associated tau disease showed largely symmetric frontotemporal atrophy, whereas PGRN-associated, tau-negative disease showed asymmetric degeneration. The paper does not establish an association specifically between NFT deposition and grey-matter atrophy, or compare distinctive atrophy patterns across different tauopathies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [7] source

      The Abstract (page unavailable) says that MRI-detected cortical atrophy parallels the spread of Alzheimer’s disease pathology and that atrophy arises from neuron and synapse loss. It does not specifically link atrophy to NFT deposition or establish distinct atrophy patterns across different tauopathies. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Findingown data

    The high-resolution FA maps show clearly white matter structures that are highly anisotropic, like the CC, AC, and hippocampal commissure (HC).

    “The highresolution FA maps show clearly white matter structures that are highly anisotropic, like the CC and the AC and hippocampal commissure (HC).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    FA was decreased in most brain regions, while MD, RD, and AD were increased in homozygotes compared to hemizygotes and non-transgenic littermates.

    “FA was found to be decreased in most brain regions, while MD, RD, and AD were increased in homozygotes compared to hemizygotes and non-transgenic littermates.”
    • Also stated in: § Discussion/Conclusion · plain
      “ABA showed that decreased FA in most brain regions, while MD, RD, and AD were increased in homozygous P301L mice compared to hemizygous and non-transgenic littermates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    VBA found pronounced and brain-wide spread changes when comparing homozygous P301L mice with non-transgenic littermates, which were not seen when comparing hemizygous P301L with non-transgenic animals.

    “With VBA, we found pronounced and brain-wide spread changes when comparing homozygous, P301L mice with non-transgenic littermates, which were not seen when comparing hemizygous P301L with non-transgenic animals.”
    • Also stated in: § VBA Reveals Gene-Dose-Dependent Effects on DTI Metrics · plain
      “Firstly, we compared hemizygous P301L mice with non-transgenic littermates, but no different changes between the 2 groups were observed.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In ABA, RD values were significantly increased in the AC, CC, CPD, HPR, SUB, and TH in homozygous P301L mice compared to hemizygotes and non-transgenic littermates.

    “RD values were significantly increased in the AC, CC, CPD, HPR, SUB, and TH in homozygous P310L mice compared to hemizygotes and non-transgenic littermates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because samples are equally treated, volume changes induced by fixation do not hamper advanced, unbiased computational approaches and allow detection of anatomical phenotypes in transgenic animals.

    “As samples are equally treated, the volume changes induced by fixation do not hamper advanced, unbiased computational approaches and allow detection of anatomical phenotypes in transgenic animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In many neurodegenerative diseases, microstructural changes occur across the whole brain, and conventional ROI analysis may miss changes in areas that are not selected.

    “Moreover, in many neurodegenerative diseases, microstructural changes occur across the whole brain, and conventional ROI analysis may miss to detect changes in areas that are not selected [49].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49]

      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).

    Premisecitation

    Brains not removed from the skull preserve cortical and central brain structure.

    “Brains were not removed from the skull, which has been shown previously to preserve cortical and central brain structure [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] source

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

    Study design and conductown data

    Variance homogeneity was tested using the Levene test, which showed regions with and without homogeneous variance.

    “Variance homogeneity was tested using the Levene test which showed regions with and without homogeneous variance.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    DTI microstructural changes seem to precede gross anatomical changes seen on structural MRI.

    “Importantly, DTI microstructural changes seem to precede gross anatomical changes seen on structural MRI [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

  • May combine two claims.

    Interpretationown data

    Changes in DTI metrics are gene-dose dependent, with homozygous P301L mice showing the phenotype.

    “The comparisons demonstrated that changes in DTI metrics are gene-dose dependent, where mice with the stronger tau transgene expression (i.e., homozygous P301L mice) show the phenotype.”
    • Also stated in: § Discussion/Conclusion · boosted
      “In summary, ex vivo DTI demonstrated brain-wide and gene-dose-dependent microstructural changes in the P301L mouse model of human tauopathy, similar to what has been observed in patients with tauopathies.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Smoothing in DTI is challenging due to thin tracts of white matter and heterogeneity of the FA maps.

    “Smoothing in DTI is also challenging due to thin tracts of white matter and heterogeneity of the FA maps.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Strong gradients for strong diffusion weighting are commonly available in small-bore animal scanners.

    “These are commonly available in small-bore animal scanners.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ABA analysis is based on automatic segmentation of brain regions defined in the atlas after normalization.

    “ABA analysis is based on automatic segmentation of brain regions defined in the atlas after normalization [51][52][53][54].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [51]

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

    • cites [52]

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

    • cites [53]

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

    • cites [54]

      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), S4 (based).

    Interpretationnone given

    Methodological differences in DTI data acquisition (in vivo vs. ex vivo and sequence parameters) and different analysis methods (ROI, VBA, ABA etc.) may contribute to observed differences in studies.

    “Furthermore, methodological differences in DTI data acquisition (in vivo vs. ex vivo and sequence parameters) and different analysis methods (ROI, VBA, ABA etc.) may contribute to the observed differences in studies.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Differences in DTI metrics in cross-sectional studies in transgenic mouse models of tauopathy based on MAPT mutations may arise due to use of different strains, type of tau mutation, promoter of transgene expression, transgene expression levels, genetic background, and housing conditions, which are known to affect phenotype.

    “Differences in DTI metrics in cross-sectional studies in transgenic mouse models of tauopathy based on MAPT mutations may arise due to the use of different strains, that is, the type of tau mutation, promoter of transgene expression, transgene expression levels, genetic background, and housing conditions [56], which are known to affect the phenotype.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56]

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

  • Classified as probably not a substantial claim.

    Premisecitation

    White matter changes are indicative of white matter damage and demyelination caused by axonal tau pathology.

    “Such observations are indicative of white matter damage and demyelination caused by axonal tau pathology [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

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

    Interpretationreasoning

    The interpretation of changes in the measured diffusion tensor is awaiting histological determination.

    “The interpretation of changes in the measured diffusion tensor is thus awaiting histological determination.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The reduced diffusivity of fixed tissue requires strong gradients for strong diffusion weighting.

    “The reduced diffusivity of fixed tissue requires strong gradients for strong diffusion weighting.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The DTI analysis pipeline may serve for the phenotyping of models of tauopathy and other brain diseases.

    “The DTI analysis pipeline may serve for the phenotyping of models of tauopathy and other brain diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ABA provides high sensitivity to small and widely distributed changes, but fails when regions are not within the anatomical boundaries of the predefined atlas.

    “This provides high sensitivity to small and widely distributed changes, but it fails when the regions are not within the anatomical boundaries of the predefined atlas [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54]

      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).

    Interpretationreasoning

    VBA's statistical power is poor due to the high level of noise.

    “Besides, its statistical power is poor due to the high level of noise.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Studies in patients with mild cognitive impairment have shown that changes in DTI metrics in the hippocampus can predict cognitive decline and constitute a more sensitive predictor than changes in hippocampal volume.

    “Studies in patients with mild cognitive impairment have shown that changes in DTI metrics in the hippocampus, a region involved in working memory formation can predict cognitive decline and constitute a more sensitive predictor than changes in hippocampal volume [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

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

    Study design and conductnone given

    All experiments were performed in accordance with the Swiss Federal Act on Animal Protection and were approved by the Cantonal Veterinary Office, Zurich (permit number: ZH082/18).

    “All the experiments were performed in accordance with the Swiss Federal Act on Animal Protection and were approved by the Cantonal Veterinary Office, Zurich (permit number: ZH082/18).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    DTI is increasingly used to assess microstructural changes in the grey matter.

    “DTI is also increasingly used to assess microstructural changes in the grey matter [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55]

      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).

    Study design and conductnone given

    All procedures fulfilled the ARRIVE guidelines on reporting animal experiments.

    “All procedures fulfilled the ARRIVE guidelines on reporting animal experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    VBA used an unpaired two-sample t test with p < 0.001 and clusterwise FDR correction.

    “VBA (t values overlaid on mouse brain template) comparing homozygous P301L mice with non-transgenic littermates (unpaired two-sample t test p < 0.001, clusterwise FDR correction).”
    Quote in the paperSubstantial claim
41 of 41

  • The authors state this as an assumption.

    Each individual voxel represents the same anatomical location of the brain across normalized images.

    “with the assumption that each individual voxel represents the same anatomical location of the brain [49,51,52].”

  • The paper relies on this without support.

    VBA does not inform about the direction of DTI metric changes.

    “While the VBA revealed areas of significant changes in DTI metrics, it does not inform about the direction of the changes.”
2 of 2

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?

  • The lack of significant changes in ac among ages 4-12m is consistent with a recent study using the P301L mouse model.

    “which is consistent with a recent study using the P301L mouse model (Massalimova et al., 2021).”

    From Age-dependent microstructure alterations in 5xFAD mice by high-resolution diffusion tensor imaging (2022) · cites this paper as Massalimova et al., 2021

    The Fractional Anisotropy section reports no difference in anterior-commissure (AC) FA between groups, which is consistent with an absence of change in that measure. But the Animal Models section describes only 8.5-month-old mice, not a comparison across 4–12 months, and Table 1 reports significant AC changes in other diffusion measures. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Previous DTI studies have demonstrated WM integrity impairment in various types of AD mouse models.

    “Previous DTI studies have demonstrated WM integrity impairment in various types of AD mouse models (Qin et al., 2013; Massalimova et al., 2020; Bergamino et al., 2023).”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Massalimova et al., 2020

    The Discussion/Conclusion (p. 8) reports DTI-detected white-matter changes in homozygous P301L mice, supporting the white-matter impairment attributed to this study. The paper identifies P301L as a model of human tauopathy, not specifically an AD mouse model, and reports no comparable changes in hemizygous mice. The other citations may address the sentence’s reference to various models, but this source alone does not establish that breadth. (LLM, conf=0.85)

    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.

  • Hemizygous FA is described as reduced where the table shows higher values

    Major

    The text says FA is reduced in hemizygous mice in the CPD and CRX, but the table shows higher hemizygous means than non-transgenic means in both regions (0.61 versus 0.55 and 0.29 versus 0.28). Neither hemizygous FA entry is marked as significantly different from non-transgenic littermates.

  • CPD radial diffusivity change has the opposite direction

    Major

    The text reports increased RD in hemizygous mice compared with non-transgenic littermates. The table instead shows a significantly lower hemizygous value, 0.05 versus 0.08.

  • Discussion calls other white matter regions unchanged despite reported changes

    Major

    The discussion says white matter regions other than the CC were unchanged, whereas the results report significantly increased MD in both the AC and CPD in homozygotes.

  • Thalamic radial diffusivity is lower, not higher, in homozygotes than hemizygotes

    Minor

    The text describes a significant increase in TH RD in homozygotes relative to hemizygotes, but the table reports 0.13 for homozygotes and 0.14 for hemizygotes. Its # marker also denotes a significant difference for that comparison.

  • Claimed cortical FA and RD changes versus controls lack table significance markers

    Minor

    The discussion describes decreased cortical FA and increased cortical RD in homozygotes compared with non-transgenic controls. In the table, both homozygous CRX entries carry only #, denoting a comparison with hemizygotes, and neither carries the * denoting a comparison with non-transgenic littermates.

5 of 5

Cites

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Cited by

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Related

Authors
Massalimova, A., Ni, R., Nitsch, R. M., Reisert, M., von Elverfeldt, D., & Klohs, J.
ORCID
Ni, Ruiqing
Venue
Neurodegenerative Diseases
Publisher
S. Karger AG
Published
2020
Volume
20
Issue
5-6
Pages
173-184
ISSN
  • 1660-2854 (ISSN-L)
  • 1660-2862
DOI
10.1159/000515754
OpenAlex
W3160614797
Cited by
28
References
68
Citations by year
2025: 1 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 8
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurodegenerative Diseases (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
  • ETH Zürich Research Collection
  • Zurich Open Repository and Archive (University of Zurich)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32NE30_173678/1, 179277)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
diffusion tensor imaging, white matter microstructure, gray matter microstructure, fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, voxel-based analysis, Allen Mouse Brain Atlas, neurofibrillary tangles, hyperphosphorylated tau, ex vivo brain imaging, neurodegeneration biomarkers, Alzheimer's disease

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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