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Cited by 49Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Neuroimaging Techniques and Applications

Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease.

Open access
Manno, Francis A. M., Isla, Arturo G., Manno, Sinai H. C., Ahmed, Irfan, Cheng, Shuk Han, Barrios, Fernando A., Lau, Condon·2019·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2019.00039PMC PMC6440287
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Abstract

Alzheimer's disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In 2-month-old 3xTg-AD mice, before intraneuronal plaque accumulation, MRI detected cortical white-matter microstructural changes, enlarged lateral ventricles, and reduced interhemispheric hippocampal resting-state connectivity compared with wild-type controls. The authors propose these early imaging changes as potential prodromal biomarkers for Alzheimer’s disease.

Key findings

  • Cortical fractional anisotropy (FA) was higher in 3xTg-AD than controls (0.42 ± 0.05 vs. 0.25 ± 0.09 μm²/ms, p < 0.05), while radial diffusivity (RD λ⊥) was lower (0.46 ± 0.02 vs. 0.53 ± 0.04 μm²/ms, p < 0.05); axial diffusivity and mean diffusivity were similar.
  • Lateral ventricular volume was about four times larger in 3xTg-AD mice (5.39 ± 2.20 mm³) than controls (1.40 ± 0.20 mm³, p < 0.001).
  • Interhemispheric hippocampal resting-state functional connectivity was lower in 3xTg-AD mice (0.14 ± 0.03) than controls (0.49 ± 0.17, p < 0.01), whereas caudate putamen connectivity was similar (0.37 ± 0.12 vs. 0.36 ± 0.22).
  • Voxel-based DTI showed widespread cortical FA increases and RD decreases spanning Bregma −4.6 to −7.0 mm, covering visual, auditory, and somatosensory cortices.

Methods

  • Ten female 3xTg-AD mice and 10 wild-type controls, approximately 8 weeks old and ~35 g, underwent 7T MRI with DTI, resting-state fMRI, and volumetry.
  • DTI metrics were analyzed with voxel-based statistics and region-of-interest analysis in cortex and hippocampus; lateral ventricle volume was delineated on RD maps at Bregma −3.0 and −3.8 mm.
  • Resting-state fMRI used seed-based analysis with hippocampal and caudate putamen seeds; interhemispheric connectivity was quantified by correlation coefficients, and group comparisons used t-tests with p < 0.05 unless otherwise noted.

Limitations

  • Stated: the study examined only an early time point, so longitudinal studies are needed; only female mice were used and estrus cycle was not recorded; structural-functional correlations were not performed; the rsfMRI correlation threshold of 0.35 was chosen empirically, and future work could use Bayesian approaches, different smoothing, ALFF, or ICA.
  • Evident from the text: the sample size was small (10 per group), and the single-sex, single-age design limits generalization to male mice or to later disease stages.

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

Integrity signals

Registry

Crossref · 10.3389/fnagi.2019.00039

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

28 of 48 cited sources checked · 13 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    There exists no effective diagnostic biomarker that can detect the prodromal features of AD before the emergence of cognitive alterations.

    “there exists no effective diagnostic biomarker that can detect the prodromal features of AD before the emergence of cognitive alterations (Cavedo et al., 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Cavedo et al., 2014 source

      The Abstract says biological markers can detect AD-related abnormalities years before overt clinical symptoms and that six biomarkers are sufficiently validated for inclusion in diagnostic criteria. The ‘Value of multimodal imaging in prevention trials’ section qualifies this: reliable staging before clinical onset may require a combination of biomarkers. That qualification does not support the categorical claim that no effective diagnostic biomarker exists. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    The 3xTg-AD mouse has cognitive decline particularly in long term memory.

    “intraneuronal Aβ accumulation and cognitive decline particularly in long term memory (Bittner et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bittner et al., 2010 source

      The Discussion (page unavailable) says that 3xTg-AD mice show cognitive decline as early as 4–6 months and describes intracellular accumulation of oligomeric Aβ. It does not specify that the decline is particularly in long-term memory. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The FA increase observed in the 3xTg-AD is different from previous reports in humans and mouse models.

    “Here, the FA increase observed is different from previous reports in humans (Sexton et al., 2011) and mouse models (Sun et al., 2005, 2014; Snow et al., 2017), which could represent a rise before the fall; rising in FA prior to AD onset and falling during plaque build-up (Sun et al., 2005, 2014; Snow et al., 2017).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Sexton et al., 2011 source
    • cites Sun et al., 2005, 2014

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

    • cites Snow et al., 2017 source

      The Discussion reports decreased hippocampal FA in 3xTg mice, supporting the comparison with the citing paper’s observed increase. It also reports plaques in the affected hippocampus, but does not establish that FA rises before AD onset and then falls during plaque build-up; that temporal sequence is not supported by Snow et al. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Reduced functional connectivity in the hippocampus could be a marker preceding cognitive decline.

    “Here reduced FC could be a marker preceding cognitive decline (Sheline and Raichle, 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sheline and Raichle, 2013 source
  • Premisecitation

    Recent evidence indicates that the 3xTg-AD displays early changes in neuronal network and synaptic function, before the appearance of cognitive and physiological alterations.

    “Nevertheless, recent evidence indicates that the 3xTg-AD displays early changes in neuronal network and synaptic function, before the appearance of cognitive and physiological alterations (Chakroborty et al., 2012; Gatta et al., 2014; Kazim et al., 2017).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Chakroborty et al., 2012 source
    • cites Gatta et al., 2014 source

      The Discussion section “Dendrite formation, synaptic plasticity, and memory” reports early changes in 3xTg-AD transcripts implicated in synaptic functioning. The paper measures gene expression, however, not neuronal-network or synaptic function directly, and it does not establish that these changes precede cognitive and physiological alterations (no page numbers provided). (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Kazim et al., 2017 source

      The Discussion reports heightened CA3 network excitability in 3-week-old 3xTg-AD mice before amyloid plaques, neurofibrillary pathology, and memory impairment. It does not establish that synaptic function changed before physiological alterations generally; network hyperexcitability is itself a physiological change. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 10

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

    Premisecitation

    In the PS1 gene familial AD M146V transgenic mouse model, hippocampal augmentation was accompanied by lateral ventricular enlargement.

    “In this study the hippocampal augmentation was accompanied by lateral ventricular enlargement (Gama Sosa et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Gama Sosa et al., 2010 source

      The section on decreased microvasculature and brain atrophy reports hippocampal atrophy, not augmentation: hippocampal volume was about 30% lower in the PS1 M146V mice than in pooled controls. The Figure 6 caption in the Discussion identifies the lateral ventricle but does not state that it was enlarged. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Resting-state functional MRI (rsfMRI) has demonstrated decreased functional connectivity (FC) in AD patients versus controls.

    “resting-state functional MRI (rsfMRI) have demonstrated decreased functional connectivity (FC) in AD patients vs. controls (Dennis and Thompson, 2014; Teipel et al., 2017).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Dennis and Thompson, 2014 source
    • cites Teipel et al., 2017 source

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

    Interpretationcitation

    The FA increase could represent a rise before the fall; rising in FA prior to AD onset and falling during plaque build-up.

    “Here, the FA increase observed is different from previous reports in humans (Sexton et al., 2011) and mouse models (Sun et al., 2005, 2014; Snow et al., 2017), which could represent a rise before the fall; rising in FA prior to AD onset and falling during plaque build-up (Sun et al., 2005, 2014; Snow et al., 2017).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Sun et al., 2005, 2014

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

    • cites Snow et al., 2017 source

      The Discussion reports decreased hippocampal FA in symptomatic 3xTg mice whose hippocampi contained both amyloid plaques and neurofibrillary tangles. It does not report FA rising before AD onset or track a subsequent fall during plaque build-up; those parts of the proposed trajectory remain unsupported. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The 3xTg-AD mouse has synaptic and cholinergic degeneration deficits.

    “synaptic and cholinergic degeneration deficits (Perez et al., 2011)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Perez et al., 2011 source

      The Discussion section reports age-dependent cholinergic neuritic dystrophy and reduced cholinergic fiber density in 3xTg-AD mice. It does not report synaptic degeneration in these mice; the synaptic findings located in our copy appear only in titles in the References section. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In the PS1 gene familial AD M146V transgenic mouse model, authors reported an average reduction in hippocampal volume of 30% compared with controls.

    “It is noteworthy, that in the PS1 gene familial AD M146V transgenic mouse model, authors reported an average reduction in hippocampal volume of 30% compared with controls (Gama Sosa et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Gama Sosa et al., 2010 source

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

    Premisecitation

    In patients with mild cognitive impairment (MCI), MRI changes include increased MD in white matter and gray matter.

    “These changes include increased MD in WM and GM (Jahng et al., 2011; Gyebnár et al., 2018)”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Jahng et al., 2011 source

      The Discussion reports higher MD in MCI than in cognitively normal subjects in several specific regions, but it does not establish increases in both white and gray matter. The Results and Discussion state that the overall MCI–normal comparisons found no significant MD differences; the paper’s reported increases in both tissue types primarily concern Alzheimer’s disease, not MCI. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Gyebnár et al., 2018 source

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

    Premisecitation

    The 3xTg-AD mouse has intraneuronal Aβ accumulation.

    “intraneuronal Aβ accumulation and cognitive decline particularly in long term memory (Bittner et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bittner et al., 2010 source

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

    Premisecitation

    Diffusion tensor imaging (DTI) has demonstrated increased mean diffusivity (MD) associated with the hippocampus and gray matter atrophy in AD patients.

    “Diffusion tensor imaging (DTI) has demonstrated increased medial diffusivity (MD) associated with the hippocampus and gray matter (GM) atrophy in AD patients (Oishi et al., 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Oishi et al., 2011 source

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

    Premisecitation

    Another study of an overlapping age range (12-14 months) found that the 3xTg-AD developed decreases in FA and axial diffusivity (AD λ//).

    “but in another study of an overlapping age range (12–14 months) the 3xTg-AD developed decreases in FA and axial diffusivity (AD λ//; Snow et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Snow et al., 2017 source

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

    Premisecitation

    The caudate putamen (CPu) was similar in size to the overall hippocampus and little FC alteration in the 3xTg-AD model was suspected in comparison to the known hippocampal alterations.

    “The CPu was used as a FC control for SBA analysis as it was similar in size to the overall hippocampus and little FC alteration in the 3xTg-AD model was suspected in comparison to the known hippocampal alterations (Oddo et al., 2003; Oishi et al., 2011; Shah et al., 2016, 2018).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Oddo et al., 2003 source
    • cites Oishi et al., 2011 source

      In “WHAT IS THE POTENTIAL OF DTI TO EVALUATE THE AD BRAIN?” (page not available), the paper reports hippocampal abnormalities in Alzheimer’s disease. It does not address CPu size, its use as a functional-connectivity control, or expected connectivity changes in the 3xTg-AD model. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Shah et al., 2016, 2018

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

  • May combine two claims.

    Interpretationcitation

    Ventricle enlargement could represent a prodromal feature related to AD that could be used as an early predictor of disease progression.

    “Together this result indicates that ventricle enlargement could represent a prodromal feature related to AD that could be used as an early predictor of disease progression (Carlson et al., 2008; Weiner, 2008).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Carlson et al., 2008 source
    • cites Weiner, 2008 source

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

    Premisecitation

    In humans, lateral ventricular enlargement was found to be a prominent feature in AD.

    “In humans, lateral ventricular enlargement was found to be a prominent feature in AD (Cash et al., 2015)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Cash et al., 2015 source

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

    Premisecitation

    Some preclinical AD data has indicated altered rsfMRI FC resulting in a loss of connectivity in the default mode network and salience network, and this finding correlates with Aβ plaque accumulation, resulting in decreased connectivity between the precuneus and hippocampus.

    “Some preclinical AD data has indicated altered rsfMRI FC (Sheline and Raichle, 2013) resulting in a loss of connectivity in the default mode network and salience network (Brier et al., 2012) and this finding correlates with Aβ plaque accumulation, resulting in decreased connectivity between the precuneus and hippocampus (Sheline et al., 2010).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Sheline and Raichle, 2013 source
    • cites Brier et al., 2012 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Sheline et al., 2010 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Recent evidence in patients indicates that this increase in FA could be related to soluble Aβ rising in the early stage of AD.

    “Recent evidence in patients indicates that this increase in FA could be related to soluble Aβ rising in the early stage of AD (Racine et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Racine et al., 2014 source

      The Results (Region of interest; Whole brain) report higher FA in participants with greater amyloid burden, consistent with an association in preclinical AD. But the paper measured amyloid deposition using PiB PET, not rising soluble Aβ, and the Discussion states that all participants were cognitively normal rather than patients with symptomatic AD. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Working and reference memory rely on efficient hippocampal connectivity between cortical areas.

    “Working and reference memory rely on efficient hippocampal connectivity between cortical areas (Jones and Wilson, 2005).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Jones and Wilson, 2005 source

      The Discussion reports functional connectivity between the hippocampus and prefrontal cortex during a spatial working-memory task, supporting the working-memory portion of the claim. Our copy does not establish that reference memory relies on this connectivity, nor that the observed coordination is necessary for either form of memory. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingnone given

    Although connectivity in the CPu between the 3xTg-AD and controls was not significantly different, the network pattern was altered.

    “Although connectivity in the CPu between the 3xTg-AD and controls was not significantly different, the network pattern was altered.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Vital signs were within normal physiological ranges throughout the duration of the experiment.

    “Vital signs were within normal physiological ranges (rectal temperature: 36.5–37.5°C, heart rate: 350–420 beats/min, breathing: 54–56 breaths/min, oxygen saturation: ~95%, end-tidal CO2: ~40 mmHg) throughout the duration of the experiment (Chan et al., 2009; Lau et al., 2011; Cheung et al., 2012a,b; Zhou et al., 2014).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control mice were wild type non-transgenic of the same age and weight as 3xTg-AD mice.

    “Control mice were wild type non-transgenic of the same age and weight as 3xTg-AD mice.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    One study found that the 3xTg-AD does not develop MRI detectable changes in late-life (11-17 months).

    “In one study, the 3xTg-AD does not develop MRI detectable changes in late-life (11–17 months; Kastyak-Ibrahim et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kastyak-Ibrahim et al., 2013 source

  • May combine two claims.

    Premisecitation

    At 2 months of age, Aβ deposition has not altered hippocampal functioning and the animals do not display long term memory alterations.

    “Here Aβ deposition has not altered hippocampal functioning and the animals do not display long term memory alterations (Sterniczuk et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sterniczuk et al., 2010 source

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

    Study design and conductnone given

    The lateral ventricle was delineated using the RD λ⊥ map of each mouse to minimize the partial volume effect of gray and white matter structures.

    “The lateral ventricle on slices Bregma −3.0 and −3.8 mm was delineated using the RD λ⊥ map of each mouse to minimize the partial volume effect of gray and WM structures.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Female mice have a greater Aβ burden.

    “Female mice were used as they have a greater Aβ burden (Carroll et al., 2007, 2010a,b; Hirata-Fukae et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carroll et al., 2007, 2010a,b

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

    • cites Hirata-Fukae et al., 2008 source

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

    Premisecitation

    A meta-analysis of DTI studies found that fractional anisotropy (FA) was decreased in AD in all regions except the parietal white matter and internal capsule.

    “A meta-analysis of DTI studies found that fractional anisotropy (FA) was decreased in AD in all regions except the parietal white matter (WM) and internal capsule (Sexton et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sexton et al., 2011 source

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

    Premisecitation

    In patients with MCI, MRI changes include a reduction in FA.

    “and a reduction in FA (Gyebnár et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gyebnár et al., 2018 source

  • May combine two claims.

    Premisecitation

    The 3xTg-AD mouse harbors presenilin 1 (PS1; M146V), amyloid precursor protein (APP; Swe), and tau(P301L) transgenes and progressively develops the pathology associated with human AD.

    “One of the most studied animal model of AD is the triple transgenic mouse model of AD (3xTg-AD) harboring presenilin 1 (PS1; M146V), amyloid precursor protein (APP; Swe), and tau(P301L) transgenes that progressively develops the pathology associated with human AD (Oddo et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oddo et al., 2003 source

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

    Premisecitation

    In the APP/PS1 mouse model of AD, significant FA and AD λ// increase was found in the cingulate cortex and striatum; FA increases in the thalamus, MD and RD λ⊥ increases in the bilateral neocortex, and FA increases in the left hippocampus.

    “As an example, in the APP/PS1 mouse model of AD a significant FA and AD λ// increase was found in the cingulate cortex and striatum; in addition to FA increases in the thalamus, MD and RD λ⊥ increases in the bilateral neocortex, and FA increases in the left hippocampus (Shu et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shu et al., 2013 source

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

    Premisecitation

    In the 3xTg-AD model, at later time points, no significant difference in FA compared with control mice was detectable.

    “or no significant difference in 3xTg-AD mice compared with control mice was detectable (Kastyak-Ibrahim et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kastyak-Ibrahim et al., 2013 source

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

    Study design and conductnone given

    The present study did not note the estrus cycle of the 3xTg-AD mice.

    “The present study, did not note the estrus cycle of our 3xTg-AD mice”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A meta-analysis of DTI studies indicated FA was decreased in AD in all regions except the parietal WM and internal capsule.

    “Furthermore, a meta-analysis of DTI studies indicated FA was decreased in AD in all regions except the parietal WM and internal capsule (Sexton et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sexton et al., 2011 source

  • May combine two claims.

    Premisecitation

    During AD development there exists a reorganization of neuronal network connectivity, not only a generalized reduction, but an adaptive response due to pathological changes.

    “The finding correlates with evidence that during AD development there exists a reorganization of neuronal network connectivity, not only resembling a generalized reduction, but an adaptive response due to pathological changes (Dubovik et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dubovik et al., 2013 source
30 of 30

  • The paper relies on this without support.

    The 3xTg-AD mouse model is a valid model of prodromal Alzheimer's disease pathology.

    “the 3xTg-AD mouse model displays a reduction in interhippocampal connectivity”

  • The paper relies on this without support.

    2 months of age in 3xTg-AD mice corresponds to a prodromal stage of Alzheimer's disease.

    “at a prodromal stage of the disease in the 3xTg-AD model (2.0 months)”

  • The paper relies on this without support.

    MRI metrics (FA, RD, rsfMRI FC) in mice are translatable to human AD.

    “for clinical translation”
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?

  • Other studies conducted on the same model in mice at ages 2, 12, and 14 months identified significant WM alterations.

    “Conversely, other studies conducted on the same model in mice at ages 2, 12, and 14 months identified significant WM alterations (Manno et al., 2019; Nie et al., 2019; Falangola et al., 2021).”

    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 Manno et al., 2019

    The Introduction and Results (Structural Alterations Underlying Alzheimer’s Disease Assessed by DTI; page not specified) report significant diffusion-measure changes in 2-month-old 3xTg-AD mice. Those passages locate the changes in cortical regions, however, rather than clearly identifying them as white-matter alterations. This paper supports the 2-month finding, not the 12- or 14-month ages associated with the other citations. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • 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).”

    From Age-dependent microstructure alterations in 5xFAD mice by high-resolution diffusion tensor imaging (2022) · cites this paper as Manno et al., 2019

  • Sample sizes were not predetermined using statistical methods, but were similar to those reported in previous publications.

    “Sample sizes were not predetermined using statistical methods; however, our sample sizes are similar to those reported in previous publications (Manno et al., 2019; Rollins et al., 2019; Güell-Bosch et al., 2020).”

    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 Manno et al., 2019

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.

  • Voxel-cluster cutoff is stated two ways

    Minor

    The methods require clusters larger than three voxels, while the results include clusters with at least three voxels. A cluster of exactly three voxels qualifies under the latter rule but not the former.

  • Hippocampal change is described as both reduction and augmentation

    Minor

    The discussion describes a 30% reduction in hippocampal volume in the cited study, then calls the hippocampal change in that study an augmentation.

2 of 2

Cites

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Cited by

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Related

Authors
Manno, F. A. M., Isla, A. G., Manno, S. H. C., Ahmed, I., Cheng, S. H., Barrios, F. A., & Lau, C.
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2019-03-22
Volume
11
Pages
39-39
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2019.00039
PMC
PMC6440287
OpenAlex
W2934816646
Semantic Scholar
20d555fe5846244d48177df278dbfb94489fd2d7
Cited by
49
References
71
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 5 · 2018: 1
FWCI
3.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • CityU Scholars (submittedVersion, cc-by)
Funders
Consejo Nacional de Ciencia y Tecnología (578458)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
Keywords
Alzheimer's disease, 3xTg-AD mice, white matter microstructure, hippocampal connectivity, interhemispheric connectivity, caudate-putamen, ventriculomegaly, fractional anisotropy, radial diffusivity, resting-state functional connectivity, preclinical biomarkers

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.

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

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