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Cited by 12Advanced Neuroimaging Techniques and ApplicationsAdvanced MRI Techniques and ApplicationsAlzheimer's disease research and treatments

Age-dependent microstructure alterations in 5xFAD mice by high-resolution diffusion tensor imaging

Open access
Maharjan, Surendra, Tsai, Andy P., Lin, Peter B., Ingraham, Cynthia, Jewett, Megan R., Landreth, Gary E., Oblak, Adrian L., Wang, Nian·2022·Frontiers in Neuroscience
DOI 10.3389/fnins.2022.964654PMC PMC9428354
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Abstract

Purpose: To evaluate the age-dependent microstructure changes in 5xFAD mice using high-resolution diffusion tensor imaging (DTI). Methods: The 5xFAD mice at 4, 7.5, and 12 months and the wild-type controls at 4 months were scanned at 9.4T using a 3D echo-planar imaging (EPI) pulse sequence with the isotropic spatial resolution of 100 μm. The b-value was 3000 s/mm 2 for all the diffusion MRI scans. The samples were also acquired with a gradient echo pulse sequence at 50 μm isotropic resolution. The microstructure changes were quantified with DTI metrics, including fractional anisotropy (FA) and mean diffusivity (MD). The conventional histology was performed to validate with MRI findings. Results: The FA values (p = 0.028) showed significant differences in the cortex between wild-type (WT) and 5xFAD mice at 4 months, while hippocampus, anterior commissure, corpus callosum, and fornix showed no significant differences for either FA and MD. FA values of 5xFAD mice gradually decreased in cortex (0.140 ± 0.007 at 4 months, 0.132 ± 0.008 at 7.5 months, 0.126 ± 0.013 at 12 months) and fornix (0.140 ± 0.007 at 4 months, 0.132 ± 0.008 at 7.5 months, 0.126 ± 0.013 at 12 months) with aging. Both FA (p = 0.029) and MD (p = 0.037) demonstrated significant differences in corpus callosum between 4 and 12 months age old. FA and MD were not significantly different in the hippocampus or anterior commissure. The age-dependent microstructure alterations were better captured by FA when compared to MD. Conclusion: FA showed higher sensitivity to monitor amyloid deposition in 5xFAD mice. DTI may be utilized as a sensitive biomarker to monitor beta-amyloid progression for preclinical studies.

AI snapshot

Written from the paper’s full text.

TL;DR

High-resolution ex vivo DTI at 100 μm detected age-dependent microstructural changes in 5xFAD mice, with FA more sensitive than MD. FA was significantly lower in cortex at 4 months and declined with age in cortex and fornix, while corpus callosum showed FA and MD differences between 4 and 12 months.

Key findings

  • At 4 months, cortex FA significantly differed between WT and 5xFAD mice (p = 0.028); cortex MD did not (p = 0.052). The abstract reports no significant FA/MD differences in hippocampus, anterior commissure, corpus callosum, or fornix, although the Results list hippocampal MD p = 0.007.
  • In 5xFAD mice, FA decreased with age in cortex (0.140 ± 0.007 at 4 months, 0.132 ± 0.008 at 7.5 months, 0.126 ± 0.013 at 12 months) and fornix (same reported values). Corpus callosum showed significant FA (p = 0.029) and MD (p = 0.037) differences between 4 and 12 months.
  • Whole-brain ROI analysis found FA captured more age effects than MD. At 4 vs. 7.5 months, significant FA differences appeared in insular cortex, V1M, V2L, Au1, and fornix; at 4 vs. 12 months, additional FA differences appeared in M1, M2, LO, AuD, V1B, DIEnt, corpus callosum, and striatum. MD showed fewer changes: no cortex differences at 4 vs. 7.5 months, significant differences in striatum and corpus callosum at 4 vs. 12 months, fornix differences in both comparisons, and no anterior commissure differences.
  • Histology showed beta-amyloid plaques increased with age in cortex and hippocampus; FA reductions corresponded to plaque accumulation in cortical layers and hippocampal DG, DS, and CA2 regions.

Methods

  • Ex vivo mouse brains were studied: WT and 5xFAD mice, with 5xFAD at 4, 7.5, and 12 months and WT at 4 months. Scans used a 9.4T magnet, 3D EPI at 100 μm isotropic resolution, b = 3000 s/mm², 61 diffusion directions, and six b0 measurements; a GRE sequence at 50 μm isotropic resolution was also acquired. Histology used NeuN and 6E10 staining.
  • DTI metrics included FA, MD, AD, and RD, calculated with DSI Studio. Brains were registered to the Waxholm atlas and divided into 166 ROIs. One-way ANOVA compared WT vs. 5xFAD at 4 months and 5xFAD ages (4 vs. 7.5 months, 4 vs. 12 months), with significance at p < 0.05.

Limitations

  • Stated: only ROI-based analysis was performed due to limited sample size; voxel-based analysis with larger samples is needed. Ex vivo fixation may not accurately represent normal physiological tissue microstructure. Only female 5xFAD mice were studied, so sex differences require future work. Transgenic models have limited correspondence to human AD.
  • Evident: the text contains an inconsistency for hippocampal MD at 4 months—the abstract says no significant differences, while the Results report p = 0.007. The abstract also reports identical FA values for cortex and fornix, which may be a reporting error.

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

Integrity signals

Registry

Crossref · 10.3389/fnins.2022.964654

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

36 of 47 cited sources checked · 21 supported · 1 flagged · accuracy not yet measured

  • Interpretationcitation

    The heterogeneous FA alterations in the hippocampus may be associated primarily with plaque deposition and related inflammation.

    “which may be associated primarily with the plaque deposition and related inflammation (Praet et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Praet et al., 2018 source

      The Discussion (page unavailable) links hippocampal changes in APP/PS1 mice primarily to Aβ-induced inflammation, but the change was in mean diffusivity, not FA; the authors explicitly report no hippocampal FA change. The Results (page unavailable) report FA correlations with amyloid and inflammatory markers in the motor cortex, not the hippocampus. The source therefore does not establish the proposed explanation for heterogeneous hippocampal FA alterations. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    DTI changes precede anatomical changes on structural MRI for detecting brain impairment in different mice models.

    “Several studies have demonstrated that DTI changes precede the anatomical changes on structural MRI for detecting the brain impairment in different mice models (Zhang et al., 2012; Muller et al., 2020).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Zhang et al., 2012 source

      The ‘Using DTI to study white matter injury’ section reports DTI-detected abnormalities in rodent disease models, including an early diffusivity change in a mouse injury model. It does not compare the timing of those changes with anatomical changes on structural MRI, so the claimed precedence is unsupported. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Muller et al., 2020 source

      The section on AD animal models reports that DTI detects abnormalities in several mouse models, including changes detected as early as 2.5 months in a tauopathy model (page unavailable). It does not establish that those DTI changes precede anatomical changes visible on structural MRI; the Discussion describes longitudinal DTI findings without making that comparison. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Fornix can be used as a disease biomarker for pharmacological therapeutics.

    “and can be used as a disease biomarker for pharmacological therapeutics (Badea et al., 2016).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Badea et al., 2016 source
  • Interpretationcitation

    Compared to other white matter bundles, fornix may play an important role in AD pathology.

    “Compared to other white matter bundles, fornix may play an important role in AD pathology”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Badea et al., 2016 source
  • Premisecitation

    Fornix microstructural degradation may provide evidence of degenerative white matter injury in AD.

    “and may provide evidence of degenerative white matter injury in AD (Lee et al., 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lee et al., 2012 source
  • Classified as probably not a substantial claim. 28
  • May combine two claims. 11

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

    Premisecitation

    FA in the cortex was reported to increase in 3xTg AD mice, while FA was reduced in APP transgenic mice.

    “For instance, FA in the cortex was reported to increase in 3xTg AD mice (Snow et al., 2017; Manno et al., 2019), while the FA was showed reduced in APP transgenic mice (Muller et al., 2013; Qin et al., 2013).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Snow et al., 2017 source

      Snow et al.’s DTI measures section reports no significant difference in cortical FA between 3xTg and control mice; Table 1 lists 0.31 versus 0.33 (p = 0.8). It reports reduced FA in the hippocampus instead. The APP-mouse clause is cited to other papers, not Snow et al. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Manno et al., 2019 source
    • cites Muller et al., 2013 source

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

    Premisecitation

    The 5xFAD mouse expresses human APP with three FAD mutations and human PSEN1 with two FAD mutations, and is commonly used to study the mechanisms of AD.

    “The transgenic mouse model, 5xFAD, expresses human APP with three FAD mutations and human PSEN1 with two FAD mutations, and is commonly used to study the mechanisms of AD (Oakley et al., 2006; Forner et al., 2021).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Oakley et al., 2006 source
    • cites Forner et al., 2021 source

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

    Premisecitation

    Patients with preclinical AD have widespread white matter abnormalities at a stage similar to those reported in AD.

    “patients with preclinical AD have widespread white matter abnormalities at a stage similar to those reported in AD (Marquez and Yassa, 2019; Stone et al., 2021).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Marquez and Yassa, 2019 source

      The “Reduced white matter integrity – Diffusion MRI” section reports widespread declines in white matter integrity in MCI and AD, and the Summary and Conclusions repeats that finding. Neither passage establishes widespread white matter abnormalities in patients with preclinical AD or says their abnormalities are similar to those in AD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Stone et al., 2021 source

      The Introduction says white-matter changes may appear early in AD, and the Discussion reports that specific tracts can be affected years before symptoms. But Stone et al. studied patients with mild cognitive impairment and identified specific tract changes; it does not establish widespread abnormalities in preclinical AD comparable to those in AD. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Decreased FA was detected in the hippocampus in the 12-14-month-old 3xTG AD mice.

    “In contrast, decreased FA was detected in the hippocampus in the 12-14-month-old 3xTG AD mice (Snow et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Snow et al., 2017 source

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

    Interpretationcitation

    Distinguishing individual amyloid plaques by high-resolution MRI might provide a noninvasive estimate of plaque burden in transgenic AD mice that might be useful in assessing the efficacy of anti-amyloid therapies.

    “Distinguishing individual amyloid plaques by high-resolution MRI might provide a noninvasive estimate of plaque burden in transgenic AD mice that might be useful in assessing the efficacy of anti-amyloid therapies (Santin et al., 2016).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Santin et al., 2016 source

      The Conclusion reports that Gd-stained MRI monitored individual plaques longitudinally and tested an anti-amyloid immunotherapy in APP/PS1 mice; the Methods describe quantifying plaque load from the images. However, the Discussion says the method requires intracerebroventricular contrast-agent administration, so the claim’s description of the approach as noninvasive is not supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In 5xFAD mice, amyloid plaques are first observed between two and four months of age in the cortical layer V and in the subiculum of the hippocampal formation.

    “In 5xFAD mice, amyloid plaques are first observed between two and four months of age in the cortical layer V and in the subiculum of the hippocampal formation (Oblak et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Oblak et al., 2021 source

      The Results section, “Whole Brain Imaging and Quantification of Plaque Progression” (page not provided), reports plaques in 5XFAD mice by two months, with high densities in the hippocampal formation. It does not identify cortical layer V or the subiculum as the sites where plaques first appear; the separate mentions of those locations concern neuron loss, not initial plaque deposition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The plaques showed hypointensity in MRI images and increased with age in both cortex and hippocampus regions, consistent with previous findings.

    “The plaques showed hypointensity in MRI images and increased with age in both cortex and hippocampus regions, which is consistent with several previous findings (Higuchi et al., 2005; Meadowcroft et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Higuchi et al., 2005 source
    • cites Meadowcroft et al., 2009 source

      The Results (page unavailable) identify hypointense MRI spots as Aβ plaques in APP/PS1 mouse cortex and report plaques in the neocortex and hippocampus on histological staining. The Discussion (page unavailable) says mouse plaques are believed to grow throughout life, but the paper does not establish an age-related increase in both regions; it also says the smaller hippocampal plaques described in the Results were not visible on MRI. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The MRI signal has been enhanced by MEMRI to visualize Aβ plaques in transgenic rodent models of AD.

    “The MRI signal has been enhanced by the MEMRI to visualize the Aβ plaques in transgenic rodent models of AD (Kim et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al., 2021 source

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

    Premisecitation

    Aβ plaques could also be detected in mouse AD models using a high-resolution T2-weighted spin-echo sequence.

    “The Aβ plaques could also be detected in mouse AD models using a high-resolution T2-weighted spin-echo sequence (Jack et al., 2005).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jack et al., 2005 source

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

    Premisecitation

    Amyloid plaque loading is known to be high in the hippocampus.

    “Similar to the cortex, amyloid plaque loading is known to be high in hippocampus (Lazarov et al., 2002; Vyas et al., 2020).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Lazarov et al., 2002 source
    • cites Vyas et al., 2020 source

      The Changes in Brain Connectivity and Circuit Function section (page unavailable) describes amyloid deposits in an Alzheimer’s mouse model and discusses hippocampal deficits. It does not establish that plaque loading is high in the hippocampus or compare hippocampal loading with cortical loading. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Diffusion MRI is more sensitive to brain microstructural changes than conventional volumetric MRI and has been widely used for evaluation of white matter integrity.

    “Compared to the conventional volumetric MRI methods, diffusion MRI (dMRI) is more sensitive to the brain microstructural changes and has been widely used for the evaluation of white matter integrity (Bozzali et al., 2002; Mielke et al., 2009; Stebbins and Murphy, 2009; Wang et al., 2019b; Harrison et al., 2020; Veale et al., 2021).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Bozzali et al., 2002 source
    • cites Mielke et al., 2009 source

      The Introduction describes DTI as a method for examining white matter integrity and cites numerous studies using it, supporting the claim about its use. The Discussion says the study did not analyze other white- or gray-matter measures alongside DTI; our copy does not establish that diffusion MRI is more sensitive to microstructural changes than conventional volumetric MRI. Page numbers were not provided. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Stebbins and Murphy, 2009 source

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

    Premisecitation

    Transgenic animal models are invaluable tools for studying pathogenic mechanisms and testing therapeutics of AD.

    “transgenic animal models are an invaluable tool for studying pathogenic mechanisms and testing therapeutics of AD (Kitazawa et al., 2012; Jankowsky and Zheng, 2017; Sasaguri et al., 2017).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Kitazawa et al., 2012 source
    • cites Jankowsky and Zheng, 2017 source
    • cites Sasaguri et al., 2017 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The capability to monitor alterations in tissue microstructure caused by Aβ accumulation may provide an important biomarker to monitor disease progression or treatment response.

    “The capability to monitor the alterations in tissue microstructure caused by the accumulation of Aβ may provide an important biomarker to monitor disease progression or treatment response (Adlard et al., 2014; Thal et al., 2014).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Adlard et al., 2014 source

      In “Current status of neuroimaging biomarkers in Alzheimer's disease” (page unavailable), the review discusses MRI measures of microscopic changes and says an MTR reduction may reflect amyloid deposition, but also metabolic dysfunction. It does not establish that the monitored microstructural changes are caused by Aβ accumulation or specifically propose those changes as a biomarker of treatment response; its discussion of monitoring therapy concerns PET imaging in mice. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Thal et al., 2014 source

      The section “Amyloid PET as a predictor of clinical progression to AD dementia” (page unavailable) reports that amyloid PET uptake is associated with faster clinical worsening, supporting the potential value of an Aβ-related biomarker for tracking disease progression. It does not establish that Aβ accumulation causes measurable tissue-microstructure alterations or that monitoring those alterations tracks treatment response. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Gadolinium-stained MRI can be used to detect amyloid plaques in both mouse AD models and human-AD brains.

    “Dudeffant et al. (2017) demonstrated that Gadolinium (Gd)-stained MRI can be used to detect the amyloid plaques in both mouse AD models and human-AD brains.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Dudeffant et al., 2017 source

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

    Premisecitation

    The fornix is a white matter bundle belonging to the medial diencephalon and serves a vital role in memory functions.

    “The fornix is a white matter bundle belonging to the medial diencephalon and serves a vital role in memory functions (Copenhaver et al., 2006; Nowrangi and Rosenberg, 2015).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Copenhaver et al., 2006 source
    • cites Nowrangi and Rosenberg, 2015 source

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

    Premisecitation

    DTI studies of AD models with marked neuron loss indicate increased MD, whereas those of a mild neuropathological phenotype without neuron loss tend to report decreased MD.

    “It’s also suggested that DTI studies of AD models with marked neuron loss indicate increased MD, whereas those of a mild neuropathological phenotype without neuron loss tend to report decreased MD (Snow et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Snow et al., 2017 source

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

    Premisecitation

    White matter abnormalities, particularly axonal transport deficiencies, are important components of AD.

    “White matter abnormalities, particularly axonal transport deficiencies, are also important components of AD (Klok et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Klok et al., 2018 source

      The Introduction and Discussion address vanishing white matter disease (VWM), not AD; searches for Alzheimer’s disease and AD found no passage assessing either condition in AD. The Discussion says disturbed axonal transport does not appear to be a central problem in VWM, but that finding cannot establish or refute the claim about AD. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Transgenic models have been widely used to study AD risk factors and mechanisms.

    “transgenic models have been widely used to study AD risk factors and mechanisms”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Elder et al., 2010 source

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

    Interpretationcitation

    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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Massalimova et al., 2021 source

      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

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

    Premisecitation

    The degree of characteristics displayed by transgenic models in comparison with AD in humans is still limited.

    “the degree of characteristics displayed in comparison with AD in humans is still limited (Elder et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Elder et al., 2010 source

  • May combine two claims.

    Findingown data

    There were more plaques accumulated in the DG, DS, and CA2 regions, consistent with the reduction of FA.

    “There were more plaques accumulated in the DG, DS, and CA2 regions, which was consistent with the reduction of FA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The cortex area exhibited lower FA values and higher plaque loading in 5xFAD mice with age.

    “The cortex area exhibited lower FA values and higher plaque loading in 5xFAD mice with age”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The hippocampus exhibits complex microstructure and has been demonstrated to show laminar features due to layer-dependent FA values.

    “It has been noted that the hippocampus exhibits complex microstructure and has been demonstrated to show laminar features due to layer-dependent FA values (Wang et al., 2020b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2020b

      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

    White matter abnormalities have been widely reported in the brains of incipient and mildly afflicted individuals.

    “white matter abnormalities have been widely reported in the brains of incipient and mildly afflicted individuals (Sachdev et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sachdev et al., 2013 source

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

    Study design and conductnone given

    Animal experiments were carried out in compliance with the Indiana University Institutional Animal Care and Use Committee.

    “Animal experiments were carried out in compliance with the Indiana University Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Beta-amyloid plaques are a hallmark of AD that develop in its early stage.

    “The beta-amyloid plaques are a hallmark of AD that develop in its early stage (Reger et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reger et al., 2008 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The 5xFAD transgenic mice have been acknowledged as a useful model for better understanding the pathogenesis of human AD.

    “The 5xFAD transgenic mice have been acknowledged as a useful model for better understanding the pathogenesis of human AD (Girard et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Girard et al., 2013 source

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

    Premisecitation

    Reduced FA and increased MD in the hippocampus were reported in many human studies, probably attributed to increased extracellular space volume and neurodegeneration.

    “Reduced FA and increased MD in hippocampus were reported in many of these human studies, probably attributed to increased extracellular space volume and neurodegeneration (Muller et al., 2007; Cherubini et al., 2010; Hong et al., 2013; Nowrangi et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Muller et al., 2007 source
    • cites Cherubini et al., 2010 source
    • cites Hong et al., 2013 source

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

    Premisecitation

    Only FA showed a significant increase in the hippocampus of APP/PS1 mice, compared to other DTI metrics.

    “It has been reported that only FA showed a significant increase in the hippocampus of APP/PS1 mice, compared to other DTI metrics (Shu et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shu et al., 2013 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study only performed ROI-based analysis due to limited sample size.

    “we only performed ROI-based analysis due to the limited sample size”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Only female 5xFAD mice were used in the study.

    “only female 5xFAD mice were conducted in the study”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Ex vivo MRI may not accurately represent the tissue microstructures under normal physiological conditions due to fixation.

    “it may not accurately represent the tissue microstructures under normal physiological conditions due to the fixation.”
    Quote in the paperNot a substantial claim
32 of 32

  • The paper relies on this without support.

    Probing age-dependent tissue microstructure alterations in 5xFAD mice using high-resolution DTI has not been reported.

    “To the best of our knowledge, probing age-dependent tissue microstructure alterations in 5xFAD mice using high-resolution DTI has not been reported.”

  • The paper relies on this without support.

    The microstructure change with age in 5xFAD mice has not been investigated in detail.

    “its microstructure change with age has not been investigated in detail (Oakley et al., 2006).”

  • The paper relies on this without support.

    The 5xFAD mouse model exhibits progressive brain amyloidosis.

    “using a model of progressive brain amyloidosis”

  • The paper relies on this without support.

    DTI metrics in the 5xFAD model are sensitive to the effects of anti-AD drugs.

    “DTI metrics could be used to monitor the progression of beta-amyloid deposition and the efficiency of the anti-AD drugs.”

  • The paper relies on this without support.

    The microstructural alterations observed in 5xFAD mice are relevant to human AD.

    “the degree of characteristics displayed in comparison with AD in humans is still limited”
5 of 5

Claims other papers make about this one

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

  • Diffusion changes were most pronounced in corpus callosum, with additional alterations in cortex, hippocampal formation, and olfactory regions.

    “Diffusion changes were most pronounced in corpus callosum, with additional alterations in cortex, hippocampal formation, and olfactory regions, consistent with a prior dMRI study of AD mouse models. 48”

    From Diffusion MRI reveals amyloid plaque–associated cellular signatures through spatial transcriptomic integration (2026) · cites this paper as [48]

    The Results (Figures 6–7; page unavailable) report age-dependent diffusion changes in the corpus callosum, several cortical regions, and hippocampal subregions. They do not identify the corpus callosum as the most affected region, and a search for olfactory regions found no such finding in our copy. (LLM, conf=0.86)

    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 MD is called nonsignificant despite p = 0.007

    Minor

    The paper sets significance at p < 0.05, so the reported hippocampal MD result (p = 0.007) is significant, contrary to the statement that it is not.

  • WT figure citation includes panels labeled 5xFAD

    Minor

    The text cites Figures 1A-E for the WT mouse, but the figure caption identifies panels B-D as 5xFAD mice.

2 of 2

Cites

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Related

Authors
Maharjan, S., Tsai, A. P., Lin, P. B., Ingraham, C., Jewett, M. R., Landreth, G. E., Oblak, A. L., & Wang, N.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
Wang, Nian
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2022-08-17
Volume
16
Pages
964654-964654
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2022.964654
PMC
PMC9428354
OpenAlex
W4292304768
Cited by
11
References
75
Citations by year
2026: 4 · 2025: 3 · 2024: 2 · 2023: 2
FWCI
0.91
Type
journal article
Language
en
Update notices
corrigendum (2022-10-13)
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
National Institutes of Health (R01NS125020, RF1AG068400, U54AG054345, K01AG054753)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
5xFAD mice, Alzheimer's disease, fractional anisotropy, mean diffusivity, white matter microstructure, amyloid deposition, cerebral cortex, corpus callosum, fornix, hippocampus, anterior commissure, diffusion MRI

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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

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

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