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Cited by 7Advanced Neuroimaging Techniques and ApplicationsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study

Open access
Falangola, Maria Fatima, Nie, Xingju, Voltin, Joshua, Ward, Ralph, Dhiman, Siddhartha, Nietert, Paul J., Jensen, Jens H.·2022·Magnetic Resonance Imaging
DOI 10.1016/j.mri.2022.09.002PMC PMC9695071
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Abstract

The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer's disease (AD) with region dependent patterns of progressive amyloid-β (Aß) and tau pathology. Using diffusion MRI (dMRI), we investigated the sensitivity of dMRI measures in capturing AD pathology associated microstructure alterations in older 3xTg-AD mice, and the degree to which dMRI changes correlate with measurements of Aβ and tau pathology. 3xTg-AD and normal control (NC) mice, 15 to 21 months of age, were used in this study. In vivo dMRI data were acquired for the generation of diffusion tensor (DT) and diffusional kurtosis (DK) measures within the hippocampus and fimbria (Fi). For these same brain regions, Aβ and tau pathology were quantified by morphological analysis of Aß1-42 and AT8 immunoreactivity. Two-tailed, two-sample t-tests were performed to assess group differences in each brain region of interest (ROI), with the Benjamini-Hochberg false discovery rate (FDR) method being applied to adjust for multiple comparisons. Spearman correlation coefficients were calculated to investigate associations between diffusion and morphological measures. Our results revealed, depending on the brain region, DT and DK measures were able to detect group differences. In the dorsal hippocampus (HD), fractional anisotropy (FA) was significantly higher in the 3xTg-AD mice compared with NC mice. In the subiculum (SUB), FA, axial diffusivity (D||) and radial kurtosis (K┴) were significantly higher in 3xTg-AD mice compared with NC mice. Morphological quantification of Aß1-42 and AT8 immunoreactivity showed elevated Aß and tau in the Fi, ventral hippocampus (HV) and SUB of 3xTg-AD mice. The presence of Aβ and tau was significantly correlated with several DT and DK measures, particularly in the SUB, where an increase in tau correlated with an increase in mean kurtosis (MK) and K┴. This work demonstrates significant dMRI differences between older 3xTg-AD and NC mice in the hippocampus and Fi. Significant correlations were found between dMRI and morphological measures of Aβ and tau pathology. These results support the potential of dMRI-derived parameters as biomarkers of AD pathology. Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.

AI snapshot

Written from the paper’s full text.

TL;DR

In older 3xTg-AD mice, diffusion MRI detected region-dependent microstructural differences in the hippocampus and fimbria that correlated with Aβ and tau pathology. The results support dMRI-derived parameters as potential translatable biomarkers of AD pathology.

Key findings

  • In the dorsal hippocampus (HD), fractional anisotropy (FA) was significantly higher in 3xTg-AD mice than normal controls; higher axial diffusivity (D∥) showed a trend that did not survive FDR correction.
  • In the subiculum (SUB), FA, D∥, and radial kurtosis (K⊥) were significantly higher in 3xTg-AD mice; trends for higher FA in ventral hippocampus (HV), K∥ in fimbria (Fi), and KFA in SUB did not remain significant after FDR adjustment.
  • Morphological quantification showed significantly increased Aβ1-42 and AT8 immunoreactivity in the Fi, HV, and SUB of 3xTg-AD mice; in HD, only Aβ was significantly increased.
  • Aβ and tau presence correlated significantly with several diffusion tensor and diffusional kurtosis metrics, particularly in SUB, where increased tau correlated with increased mean kurtosis (MK) and K⊥.

Methods

  • Thirteen 3xTg-AD and eleven normal control female mice were imaged at 15, 18, and 21 months of age; in vivo dMRI was performed on a 7T Bruker scanner using a 2-shot SE-EPI DKI sequence with 30 diffusion-encoding directions and four b-values (0.5, 1.0, 1.5, and 2.0 ms/μm²).
  • ROIs were manually drawn for dorsal hippocampus, ventral hippocampus, subiculum, and fimbria; DTI and DKI metrics were calculated after motion correction, denoising, and tensor fitting.
  • After MRI, brains were stained for Aβ1-42 and AT8, immunoreactivity was quantified as optical density in matched ROIs, and analyses used two-tailed two-sample t-tests with Benjamini-Hochberg FDR correction for DT and DK metrics, Cohen’s d, and Spearman correlations between diffusion and morphology measures.

Limitations

  • The authors state that the relatively small total number of mice, especially at later ages, reduced statistical power; mice from all time points and both groups were pooled for Spearman correlations, and age-dependent changes were not assessed.
  • The authors also state that large ROIs for HD and HV may have attenuated some effects due to variability in AD pathology, and that imaging resolution was insufficient to confidently discriminate CA1 and CA3 regions.
  • Evident from the text: only female mice were used, so findings may not generalize to male 3xTg-AD mice; Spearman correlations were not adjusted for multiple comparisons.

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

Integrity signals

Registry

Crossref · 10.1016/j.mri.2022.09.002

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 38 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The authors demonstrated that dMRI measures capture the larger number of cholinergic neurons in the basal forebrain of young 3xTg-AD mice.

    “Additionally, we demonstrated that dMRI measures are able to capture the larger number of cholinergic neurons reported in the BF of these young 3xTg-AD mice [16].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Falangola MF, Nie X, Ward R, Dhiman S, Voltin J, Nietert PJ, Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer’s disease. Magn Reson Imaging 2021; 83: 1– 13. 34229088 PMC8449815 source

      The Discussion (page not provided) reports significant basal-forebrain dMRI differences in two-month-old 3xTg-AD mice and says these may be related to an increased number of cholinergic neurons. It also says the study lacks a direct correlation with morphological data, so it does not demonstrate that dMRI measures capture the larger neuron number specifically. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    The 3xTg-AD mouse provides a robust model of Alzheimer's disease with region-dependent patterns of progressive amyloid-β and tau pathology.

    “The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer’s disease (AD) with region dependent patterns of progressive amyloid-β (Aß) and tau pathology.”
    • Also stated in: § Discussion · plain
      “The 3xTg-AD mouse used in the current study provides a robust model of progressive region dependent Aß and tau pathology, with evident and sustained accumulation of plaques and tangles after 12 months of age [5, 6, 28].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ. Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010; 2010: 780102. 20798886 PMC2925282 source
    • cites [6] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 2019; 18(1): e12873. 30488653 PMC6351836 source

      The Results sections on plaques and tau pathology document age-dependent, region-specific progression, and the Discussion describes a consistent, predictable phenotype in female 3xTg-AD mice. The claim leaves that qualification out: the Animals section says only females were analyzed because males in this colony showed substantial neuropathological variability, and the Introduction notes differences among sublines. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [28] Javonillo DI, Tran KM, Phan J, Hingco E, Kramár EA, da Cunha C, Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer’s Disease. Frontiers in Neuroscience 2022; 15. PMC8818877 35140584 source
  • Premisecitation

    Previously, the authors showed that dMRI detects early myelin abnormalities in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice.

    “Previously, we have shown that dMRI is able to detect the early myelin abnormalities described in this AD mouse, particularly in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice [15].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Falangola MF, Nie X, Ward R, McKinnon ET, Dhiman S, Nietert PJ, Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3xTg-AD mice. NMR Biomed 2020; 33(9): e4346. 32557874 PMC7683375 source

      The Abstract reports dMRI differences in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice and associates them with myelin abnormalities. The Discussion reports a myelin measurement in the fimbria but says further work is needed to establish a direct correlation between dMRI and morphological findings; it does not establish that dMRI specifically detected myelin abnormalities in all three regions. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    The authors found that dMRI metrics change longitudinally with aging and AD pathology progression in several brain regions.

    “Moreover, we found that dMRI metrics change longitudinally with aging [16] and AD pathology progression [17] in several brain regions.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Falangola MF, Nie X, Ward R, Dhiman S, Voltin J, Nietert PJ, Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer’s disease. Magn Reson Imaging 2021; 83: 1– 13. 34229088 PMC8449815 source
    • cites [17] Nie X, Falangola MF, Ward R, McKinnon ET, Helpern JA, Nietert PJ, Diffusion MRI detects longitudinal white matter changes in the 3xTg-AD mouse model of Alzheimer’s disease. Magn Reson Imaging 2019; 57: 235– 42. 30543850 PMC6331227 source

      The Results report longitudinal changes in dMRI measures across several white-matter regions of 3xTg-AD mice. The Discussion suggests that some changes accompany AD-like pathology progression, but says the absence of a control group prevents separating pathology-related changes from aging; it does not establish that progression caused the measured changes. Page numbers were not provided. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The 3xTg-AD mouse develops both amyloid-β and neurofibrillary tangles in a temporal and spatial pattern similar to human AD pathology.

    “It develops both amyloid-β (Aβ) and neurofibrillary tangles in a temporal and spatial pattern similar to human AD pathology [3–6].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [3] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 2003; 24(8): 1063– 70. 14643377 source
    • cites [4] Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 2006; 281(3): 1599– 604. 16282321 source
    • cites [5] Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ. Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010; 2010: 780102. 20798886 PMC2925282 source

      The Introduction and Discussion describe age-related amyloid and tau pathology across brain regions, and the Discussion compares plaque and tangle-bearing neuron morphology with human AD. The paper does not establish that the overall temporal and spatial pattern of both pathologies matches human AD; it also notes differences in tau pathology. Page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [6] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 2019; 18(1): e12873. 30488653 PMC6351836 source
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    Only female mice were used because AD pathology development is far less pronounced and more variable in male 3xTg-AD mice.

    “Only female mice were used in this study since the development of AD pathology is far less pronounced and more variable in male 3xTg-AD mice [18,19].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [18] Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y. Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008; 1216: 92– 103. 18486110 source
    • cites [19] Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, Pike CJ. Sex differences in β-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res. 2010; 1366: 233– 45. 20934413 PMC2993873 source

      The Results section ('Female 3xTg-AD mice display higher levels of Aβ immunoreactivity than males'; page unavailable) reports greater Aβ loads and more plaques in females than in age-matched males. This supports less pronounced amyloid pathology in males, but the paper does not establish that pathology development in males is more variable. 'Only female mice were used' describes the citing study, not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    The Benjamini-Hochberg false discovery rate method was used to adjust for multiple testing of DT and DK parameters within each ROI.

    “The Benjamini-Hochberg false discovery rate (FDR) method [25] was used to adjust for multiple testing of DT (N = 4) and DK (N = 4) parameters within each ROI.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9(7): 671– 5. 22930834 PMC5554542 source

      The cited paper’s ‘Integration with other tools’ section discusses ImageJ and mentions exporting data for statistical analysis, but does not describe the Benjamini–Hochberg method or adjustments within ROIs. Searches for false discovery rate and for DT/DK parameters found no passage addressing the claim; page numbers were not available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In 3xTg-AD mice, both Aβ and tau exhibit age- and region-dependent formation, with Aβ plaques appearing prior to tangles, which are extensive in older transgenic mice.

    “Both Aβ and tau exhibit age- and region-dependent formation in these mice, with Aβ plaques appearing prior to tangles, which are extensive in older transgenic mice.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [3] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 2003; 24(8): 1063– 70. 14643377 source
    • cites [4] Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 2006; 281(3): 1599– 604. 16282321 source

      The Results section (page unavailable) describes age-dependent Aβ accumulation in the hippocampus and reports early tau pathology at 6 months and advanced tangles at 20 months. It does not establish that plaques appear before tangles or that both Aβ and tau formation are region-dependent; its explicit timing comparison is between Aβ oligomers and plaques. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [5] Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ. Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010; 2010: 780102. 20798886 PMC2925282 source

      The Discussion (page unavailable) reports that Aβ plaques increase with age and that tau pathology varies by age and brain region. Plaques were observed before filamentous tau aggregates, but the paper does not establish that tangles are extensive in older mice; its Discussion reports straight tau filaments in aged mice. It also distinguishes these late filaments from tau immunoreactivity present before plaque deposition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 2019; 18(1): e12873. 30488653 PMC6351836 source

      The Results sections on plaque accumulation and tau pathology (page unavailable) show age- and region-dependent changes in female 3xTg-AD mice: plaques first appear in the hippocampus at 6 months, and phosphorylated-tau immunoreactivity becomes extensive there at 12 and 20 months. The paper measures phosphorylated tau, not the formation or extent of tangles, so it does not establish that plaques appeared before tangles or that tangles were extensive in older mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Aβ plaque and tau pathology are evident in 15-month-old TG mice, and significantly increased with age.

    “In our morphological analysis (Fig. 2 and 3), as previously described [3–6, 28], Aβ plaque and tau pathology are evident in 15-month-old TG mice, and significantly increased with age (online supplementary Fig.1 and 2).”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [3] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 2003; 24(8): 1063– 70. 14643377 source
    • cites [4] Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 2006; 281(3): 1599– 604. 16282321 source

      The Results section (page unavailable) describes age-related Aβ accumulation in 3xTg-AD mice and tau pathology that is apparent by 6 months and advanced by 20 months. It does not specifically assess 15-month-old mice or establish a statistically significant age-related increase in both plaques and tau pathology; the citing sentence points to its own figures for that finding. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [5] Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ. Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010; 2010: 780102. 20798886 PMC2925282 source

      The Results (3.1 and 3.3; page unavailable) describe age-related increases in immunoreactivity and tau markers, and the Discussion (section 4; page unavailable) says Aβ plaque numbers increased with age. But this study did not examine 15-month-old mice—it sampled 8–9 and 18–20 months instead—and these passages do not establish a statistically significant increase in both plaque and tau pathology. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [6] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 2019; 18(1): e12873. 30488653 PMC6351836 source

      The Results sections on plaque accumulation and tau pathology report both pathologies in 12- and 20-month-old 3xTg-AD mice, with significant age-dependent increases in immunoreactivity. The paper studied 2-, 6-, 12-, and 20-month-old mice, not 15-month-old mice, so it does not directly establish the claim at that age. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [28] Javonillo DI, Tran KM, Phan J, Hingco E, Kramár EA, da Cunha C, Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer’s Disease. Frontiers in Neuroscience 2022; 15. PMC8818877 35140584 source

      The Results sections on fibrillar Aβ plaques and phosphorylated tau report age-related increases in 3xTg-AD mice. However, the paper examines mice at 4, 12, and 18 months—not 15 months—and says plaque accumulation is largely driven by females, so it does not establish the claim at the stated age for TG mice generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    At 15 months, intense pathology is present in the TG mice, including Aβ plaques, tau, myelin damage, axonal degeneration, axonal loss, and an inflammatory reaction with reactive microglia and astrocytes.

    “At 15 months, intense pathology is present in the TG mice, which includes not only Aβ plaques and tau, but also confounding factors, such as, myelin damage, axonal degeneration, axonal loss, and an inflammatory reaction with reactive microglia and astrocytes [29, 30].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [29] Lam B, Masellis M, Freedman M, Stuss DT, Black SE. Clinical, imaging, and pathological heterogeneity of the Alzheimer’s disease syndrome. Alzheimer’s Res Ther 2013; 5(1): 1. 23302773 PMC3580331 source

      The Disease topography section discusses plaques and tau-related pathology in human Alzheimer’s disease, while the white matter hyperintensities section discusses human imaging findings. Searches for 15-month-old TG mice, myelin and axonal damage, and reactive microglia and astrocytes found no passage addressing the claimed mouse pathology. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [30] Dá Mesquita S, Ferreira AC, Sousa JC, Correia-Neves M, Sousa N, Marques F. Insights on the pathophysiology of Alzheimer’s disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 2016; 68: 547– 62. 27328788 source

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

    Premisecitation

    Non-Gaussian diffusion is typically a consequence of barriers and compartments, and higher kurtosis values imply greater diffusional heterogeneity.

    “Non-Gaussian diffusion is typically a consequence of barriers and compartments, and higher kurtosis values imply greater diffusional heterogeneity [12–14].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [12] Jensen JH, Helpern JA, Ramani A, Lu H, Kaczynski K. Diffusional kurtosis imaging: the quantification of non-gaussian water diffusion by means of magnetic resonance imaging. Magn Reson Med 2005; 53(6): 1432– 40. 15906300 source

      The Special Cases section says kurtosis reflects diffusional heterogeneity in a compartment model and tends to increase with heterogeneity; it also says diffusion barriers and water exchange can alter kurtosis. The claim overstates this qualified relationship by implying that a higher kurtosis value necessarily means greater heterogeneity. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [13] Lu H, Jensen JH, Ramani A, Helpern JA. Three-dimensional characterization of non-gaussian water diffusion in humans using diffusion kurtosis imaging. NMR Biomed 2006; 19(2): 236– 47. 16521095 source
    • cites [14] Jensen JH, Helpern JA. MRI quantification of non-Gaussian water diffusion by kurtosis analysis. NMR Biomed 2010; 23(7): 698– 710. 20632416 PMC2997680 source

  • May combine two claims.

    Findingown data

    The increase of FA in the HD and SUB, and the increase of K⊥ in the SUB, were the best differentiators between the two groups in these regions.

    “As seen in Table 1, the increase of FA in the HD and SUB, and the increase K⊥ in the SUB of TG mice were the best differentiators between the two groups in these regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the fimbria (Fi), extracellular Aβ plaques correlate with a decrease in axial diffusivity (D∥) and an increase in axial kurtosis (K∥).

    “As seen in Figure 4, extracellular Aβ plaques in the Fi correlates with a decrease in D∥ and an increase K∥, while the presence of the intracellular tau pathology correlates with an increase K∥.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ1-42 and AT8 immunoreactivity was not present in normal control mice, although values for the NC group did not reach zero due to residual background stain.

    “We note that values for the NC group does not reach zero due to residual background stain, but as expected and shown in Figure 2, Aß1-42 and AT8 immunoreactivity was not present in NC mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The authors have demonstrated significant dMRI differences in older 3xTg-AD compared with normal control mice, which were significantly correlated with Aβ and tau pathology in the hippocampus and fimbria.

    “In summary, we have demonstrated significant dMRI differences in older 3xTg-AD, in comparison to NC mice, which were significantly correlated with Aβ and tau pathology in the hippocampus and Fi of the 3xTg-AD group.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    To avoid bias in the ROIs, all mouse identification numbers were randomly assigned, and the number of MRI slices sampled was consistent across mice.

    “To avoid bias in the ROIs, all the mice identification numbers were randomly assigned, and the number of MRI slices sampled was consistent across mice.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Images were acquired under the same image light and camera settings to avoid possible image intensity variation.

    “Images (4x magnification) were acquired under the same image light and camera settings to avoid possible image intensity variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Intracellular tau causes axonal clogging, leading to axonal diffusion restriction, but ultimately tau pathology results in neuronal degeneration and increase in diffusivity.

    “Intracellular tau causes axonal clogging, leading to axonal diffusion restriction, but ultimately tau pathology results in neuronal degeneration and increase in diffusivity.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Due to the small number of mice at each time point, mice from all time points and from both groups were pooled for statistical analysis, and age-dependent changes were not assessed.

    “Due to the small number of mice at each time point, mice from all time points and from both groups, were pooled for statistical analysis, and age dependent changes were not assessed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Since the imaging methods employed here are easily translatable to clinical MRI, the results of this study are also relevant to human AD.

    “Since the imaging methods employed here are easily translatable to clinical MRI, the results of this study are also relevant to human AD.”
    • Also stated in: § Abstract · plain
      “Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The imaging methods employed in this study are easily translatable to clinical MRI.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Several biological processes may contribute to the dMRI changes reported here.

    “Therefore, several biological processes may contribute to the dMRI changes reported here.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The elevated kurtosis values found by the authors and other studies are not surprising.

    “The elevated kurtosis values found by us and other studies are thus not surprising.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Extracellular Aβ aggregates change the geometry of the extracellular space, creating more barriers, increasing tissue heterogeneity, and leading to restriction of the diffusion environment.

    “Extracellular Aβ aggregates changes the geometry of the extracellular space, creating more barriers, increasing the tissue heterogeneity, and leading to restriction of the diffusion environment.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Other microstructural changes associated with AD pathology, such as neurodegeneration, may tend to lower the kurtosis.

    “Nonetheless, it should be noted that other microstructural changes associated with AD pathology, such as neurodegeneration, may tend to lower the kurtosis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No adjustment for multiple comparison corrections was done for the Spearman correlations between dMRI metrics and morphology measures.

    “Spearman correlation coefficients were calculated between the dMRI metrics and the morphology measures; no adjustment for multiple comparison corrections was done.”
    Quote in the paperNot a substantial claim
20 of 20

  • The paper relies on this without support.

    The imaging methods employed in this study are easily translatable to clinical MRI.

    “Since the imaging methods employed here are easily translatable to clinical MRI, the results of this study are also relevant to human AD.”
    “Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.”

  • The paper relies on this without support.

    Pooling mice from all time points and both groups does not confound the observed correlations between dMRI metrics and Aβ/tau pathology.

    “Due to the small number of mice at each time point, mice from all time points and from both groups, were pooled for statistical analysis, and age dependent changes were not assessed.”

  • The paper relies on this without support.

    The post-mortem morphological measurements reflect the same pathological state present during the in vivo dMRI acquisition.

    “Following the MRI scan, mice were sacrificed for morphological analysis of the degree of Aβ and tau pathology.”
3 of 3

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?

  • Myelin damage in the left dentate gyrus and right sAMY may represent key features of pathological transformation at this stage.

    “At this particular stage, myelin damage in the left dentate gyrus and right sAMY may represent key features of pathological transformation.”

    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 Falangola et al., 2022

    The Discussion (page unavailable) identifies myelin damage as one possible component of pathology in 15-month-old 3xTg-AD mice. It does not identify damage in the left dentate gyrus or right sAMY, or describe damage in those regions as key to pathological transformation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The reduced integrity observed at this stage may reflect specific pathology patterns characterized by extensive intracellular Aβ aggregates and emerging extracellular Aβ and tau immunoreactivity.

    “The reduced integrity observed at this stage may reflect specific pathology patterns characterized by extensive intracellular Aβ aggregates and emerging extracellular Aβ and tau immunoreactivity (Falangola et al., 2022).”

    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 Falangola et al., 2022

    The Results and Discussion (page unavailable) link diffusion-MRI changes in older 3xTg-AD mice to Aβ and tau pathology, and report Aβ and tau immunoreactivity. But the paper describes extracellular Aβ plaques and intracellular tau in 15-month-old mice; it does not characterize this stage by extensive intracellular Aβ aggregates or emerging extracellular Aβ and tau immunoreactivity. (LLM, conf=0.84)

    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.

  • False-discovery-rate citation points to an ImageJ paper

    Minor

    The methods cite [25] for the Benjamini-Hochberg method, but reference 25 is an ImageJ paper; the Benjamini and Yosef false-discovery-rate paper is listed as reference 27.

  • Mouse-atlas citation points to a diffusion MRI paper

    Minor

    The cited reference [24] is titled as a study of diffusion tensor estimation, not a mouse atlas. The reference list identifies a mouse brain atlas as reference 26.

  • Age-related increase claimed despite no age-dependent assessment

    Minor

    The discussion says Aβ plaque and tau pathology increased significantly with age, but the statistical methods say age-dependent changes were not assessed.

3 of 3

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Related

Authors
Falangola, M. F., Nie, X., Voltin, J., Ward, R., Dhiman, S., Nietert, P. J., & Jensen, J. H.
Affiliations
Medical University of South Carolina (US)
Corresponding author
Falangola, Maria Fatima
ORCID
Venue
Magnetic Resonance Imaging
Publisher
Elsevier BV
Published
2022-12
Volume
94
Pages
48-55
ISSN
0730-725X (ISSN-L)
DOI
10.1016/j.mri.2022.09.002
PMC
PMC9695071
OpenAlex
W4296204199
Semantic Scholar
6bafde7640f00dc5e030a20b01c02e85f964c322
Cited by
6
References
41
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 1
FWCI
0.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Magnetic Resonance Imaging (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (1RF1AG057602–01)
  • Medical University of South Carolina
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
Alzheimer's disease, 3xTg-AD mice, brain microstructure, diffusion MRI, diffusion kurtosis imaging, amyloid-beta pathology, tau pathology, hippocampus, fimbria, subiculum, fractional anisotropy, mean kurtosis, radial kurtosis, axial diffusivity, amyloid-beta 42, diffusion MRI biomarkers
MeSH terms
Correlation of Data, Aged, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, Diffusion Magnetic Resonance Imaging, 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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