CoChat
Sign Up
Cited by 70Functional Brain Connectivity StudiesAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis

Open access
Grandjean, Joanes, Schroeter, Aileen, He, Pan, Tanadini, Matteo, Keist, Ruth, Krstic, Dimitrije, Konietzko, Uwe, Klohs, Jan +2 more·2014·The Journal of Neuroscience
DOI 10.1523/jneurosci.4762-13.2014PMC PMC6608375
Open this paper in CoChat — free accountOpen PDF

Abstract

Impairment of brain functional connectivity (FC) is thought to be an early event occurring in diseases with cerebral amyloidosis, such as Alzheimer's disease. Regions sustaining altered functional networks have been shown to colocalize with regions marked with amyloid plaques burden suggesting a strong link between FC and amyloidosis. Whether the decline in FC precedes amyloid plaque deposition or is a consequence thereof is currently unknown. The sequence of events during early stages of the disease is difficult to capture in humans due to the difficulties in providing an early diagnosis and also in view of the heterogeneity among patients. Transgenic mouse lines overexpressing amyloid precursor proteins develop cerebral amyloidosis and constitute an attractive model system for studying the relationship between plaque and functional changes. In this study, ArcAβ transgenic and wild-type mice were imaged using resting-state fMRI methods across their life-span in a cross-sectional design to analyze changes in FC in relation to the pathology. Transgenic mice show compromised development of FC during the first months of postnatal life compared with wild-type animals, resulting in functional impairments that affect in particular the sensory-motor cortex already in preplaque stage. These functional alterations were accompanied by structural changes as reflected by reduced fractional anisotropy values, as derived from diffusion tensor imaging. Our results suggest cerebral amyloidosis in mice is preceded by impairment of neuronal networks and white matter structures. FC analysis in mice is an attractive tool for studying the implications of impaired neuronal networks in models of cerebral amyloid pathology.

AI snapshot

Written from the paper’s full text.

TL;DR

In ArcAβ transgenic mice, resting-state fMRI showed impaired development of functional connectivity in sensory-motor/parietal cortex during the first months of life, before dense amyloid plaque deposition. These functional changes were accompanied by altered white matter fractional anisotropy, and plaque burden did not correlate with functional connectivity.

Key findings

  • Wild-type mice developed cortical functional connectivity from z = 0.15–0.32 at 1 month to z = 0.4–0.89 at 5 months; ArcAβ mice were similar at 1 month but failed to develop these correlations by 5 months, especially in sensory-motor/parietal cortex (posterior parietal p = 3.3 × 10⁻⁹; motor p = 5.1 × 10⁻³).
  • Seed-based analysis of S1 cortex showed wild-type contralateral parietal correlation increasing from z = 0.25 to 0.6 by 5 months, whereas ArcAβ mice remained below z = 0.1 at 5, 8, and 21 months.
  • DTI revealed genotype effects on fractional anisotropy in the minor forceps, anterior external capsule, and anterior internal capsule; anterior external capsule showed genotype effect p = 1.6 × 10⁻³ and age effect p = 1.7 × 10⁻⁷.
  • Amyloid plaques were sparse at 5 months, occupied 3.2–7.4% of cortical surface at 11 months and 11.9–18% at 21 months, but plaque surface did not correlate with bilateral functional connectivity (r = 0.08).

Methods

  • Cross-sectional study of 38 ArcAβ transgenic mice (17 male, 21 female) and 36 wild-type littermates (12 male, 24 female), aged 1–21 months across four age groups; imaged at 1, 2, 5, 8, 11, 19, and 21 months, with a repeat session at 1 week.
  • 9.4 T MRI included resting-state fMRI, diffusion tensor imaging, and anatomical imaging; functional connectivity was measured as Fisher z-transformed Pearson correlations between 24 atlas ROIs, and fractional anisotropy was extracted from DTI ROIs.
  • Linear mixed models tested gender, age, genotype, and two-way interactions with likelihood ratio tests; multiple comparisons were FDR-corrected at q = 0.05 for network analysis and q = 0.15 for voxelwise analysis, with post hoc intervals of 1–5 and 5–19 months.

Limitations

  • Stated: isoflurane anesthesia may interact with amyloid-related GABAergic changes and could exacerbate effects; vascular pathology in ArcAβ mice means functional connectivity alterations may be neural, vascular, or both; poor individual-level reproducibility requires large groups or large effects.
  • Evident from the text: the cross-sectional design cannot track within-animal trajectories or establish causality, and the findings are specific to the ArcAβ model, with the authors noting that mechanisms remain elusive and that different AD mouse models show different functional connectivity patterns.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.4762-13.2014

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

21 of 45 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In mice, the somatosensory cortex appears as metabolically active as the cingulate.

    “the somatosensory cortex appears as metabolically active as the cingulate in mice (Nicholson et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Nicholson et al., 2010 source

      The Results and Discussion report glucose-uptake changes in the posterior cingulate cortex of AD-model mice, but do not compare its metabolic activity with that of the somatosensory cortex. Searches for “somatosensory” and for a comparison of somatosensory and cingulate glucose uptake found no passage addressing the claim. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The dynamics of functional connectivity alteration, both spatial and temporal, differ from patterns observed in Alzheimer's disease patients.

    “The dynamics of alteration, both spatial and temporal, differ from patterns observed in AD patients, which is marked with early altered FC in the default mode network and aggravated FC in the transition from mild cognitive impairments to AD (Greicius et al., 2004;Rombouts et al., 2005;Sorg et al., 2007;Sheline et al., 2010a,b).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Greicius et al., 2004 source

      The Results compare default-mode network activity in healthy elderly participants and patients with AD, and the Discussion reports deficient activity in the AD group. That supports a difference in the brain regions affected, but the paper does not examine temporal dynamics or worsening functional connectivity during a transition from mild cognitive impairment to AD. (LLM, conf=0.86)

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

      The fMRI data and Discussion (page unavailable) report spatial differences in default-mode deactivation between MCI and AD, as well as a different early temporal response in the anterior cingulate. They also describe deactivation as further diminished in AD. The study measured task-related BOLD deactivation, however, not functional connectivity directly or longitudinal changes during an individual's transition from MCI to AD. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Sorg et al., 2007 source

      The Abstract and Results report reduced default-mode-network functional connectivity in people with amnestic MCI, supporting the claim of early alteration. The study compares these patients with healthy controls, not with AD patients over time; the Results say a two-year follow-up was still underway. It therefore does not establish distinct spatial and temporal dynamics or worsening connectivity during the transition from MCI to AD. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The discrepancy in regional functional connectivity impairments between mice and humans might be related to a link between neuronal activity and Aβ release affecting FC strength and amyloid deposition in later life.

    “The discrepancy in regional FC impairments between mice and human might be related to a link between neuronal activity and A␤ release affecting FC strength and amyloid deposition in later life (Bero et al., 2011(Bero et al., , 2012)).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Bero et al., 2011

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

    • cites Bero et al., 2012 source

      The Discussion (page unavailable) links neuronal activity with interstitial Aβ levels and suggests an association among neural activity, functional connectivity, and later amyloid deposition in mice. It also notes a mouse–human difference in regional connectivity changes, but does not propose the neuronal-activity/Aβ link as an explanation for that discrepancy or establish Aβ release as the mechanism. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The marginal decline in FC in ArcAβ mice between 5 and 21 months is inconsistent with the observed aggravation of FC associated with transition from preclinical to clinical Alzheimer's disease.

    “but inconsistent with the observed aggravation of FC associated with transition from preclinical to clinical AD (Rombouts et al., 2005).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rombouts et al., 2005 source

      The Discussion reports that default-mode-network deactivation is altered in MCI and further affected in mild AD, supporting a worsening difference between the groups. But the study measured task-related deactivation in separate groups, not functional connectivity (FC) during an observed transition from preclinical to clinical AD. The cited passages provide no page number. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    The study could not correlate functional changes to amyloid plaque burden.

    “further, we could not correlate functional changes to amyloid plaque burden.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fractional surface occupied by amyloid plaques in the cortex is a valid measure of amyloid burden relevant to functional connectivity changes.
    • Rests on an assumption: If amyloid plaques caused functional connectivity changes, a correlation between plaque surface and functional connectivity would be detectable.
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Premisecitation

    Vasculopathy in murine models of amyloidosis has structural and functional consequences, including reduced cortical blood flow early in life and damaged capillary systems.

    “A number of structural and functional consequences of vasculopathy have been reported in murine models of amyloidosis, such as reduced cortical blood flow already early in life (He ´bert et al., 2013), as well as damaged capillary systems (Meyer et al., 2008).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites He ´bert et al., 2013

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

    • cites Meyer et al., 2008 source

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

    Premisecitation

    In humans, the default mode network is the metabolically most active network in the brain at rest.

    “Although, in humans, the DMN is the metabolically most active network in the brain at rest (Raichle et al., 2001)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Raichle et al., 2001 source

      The paper identifies an organized default mode of brain function at rest, supported by regions that decrease their activity during goal-directed tasks. But the Results and Discussion do not establish that these regions form the metabolically most active network at rest; the paper reports no activation by its resting-state definition and notes that some studied regions have oxygen consumption below the global mean. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The human brain appears organized into 10-15 networks, among which the default mode network has gained attention in Alzheimer's disease due to its colocalization with amyloid plaques.

    “Human brain appears organized into 10 -15 networks (Damoiseaux et al., 2006), among which, the default mode network (DMN) has gained attention in AD due to its colocalization with amyloid plaques (Greicius et al., 2003;Buckner et al., 2005).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Damoiseaux et al., 2006 source
    • cites Greicius et al., 2003 source

      The discussion identifies the posterior cingulate cortex as part of the default mode network and notes that it is among the earliest regions to show decreased metabolism in Alzheimer’s disease (page unavailable in our copy). It does not say that the network colocalizes with amyloid plaques or that this is why it gained attention in Alzheimer’s disease. The 10–15-network count is cited to Damoiseaux et al., not to this paper. (LLM, conf=0.84)

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

  • May combine two claims.

    Interpretationcitation

    The results compare well with growing evidence of early functional impairments in humans at risk of developing Alzheimer's disease, such as mid-life APOE4 carriers or asymptomatic elderly with amyloid deposition, and corroborate the reported absence of a correlation between amyloid plaques and functional connectivity in humans.

    “The results compare well with growing evidence of early functional impairments in humans at risk of developing Alzheimer's disease, such as mid-life APO␧4 carriers (Sheline et al., 2010a;Canuet et al., 2012) or asymptomatic elderly with amyloid deposition (Hedden et al., 2009;Sperling et al., 2009;Sheline et al., 2010b), and corroborate the reported absence of a correlation between amyloid plaques”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Sheline et al., 2010a

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

    • cites Canuet et al., 2012 source

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

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

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

    • Rests on an assumption: Early functional connectivity and fractional anisotropy changes in ArcAβ mice are relevant to human Alzheimer's disease.

  • May combine two claims.

    Interpretationcitation

    Functional connectivity deficits in ArcAβ mice appeared already robustly reduced in the early phase of life, whereas functional connectivity appeared increased in young APP/PS1 mice compared with wild-type.

    “Their results differ from ours as FC deficits in ArcA␤ mice appeared already robustly reduced in the early phase of life, whereas it appeared increased in young APP/PS1 compared with wild-type”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bero et al., 2012 source

      The Results section (page unavailable) reports higher connectivity values for young APP/PS1 than young wild-type mice in several regions, including motor and retrosplenial cortex. It does not report a direct statistical comparison between those groups, and the pattern is not consistent across all regions. This paper studies APP/PS1 mice, not the ArcAβ finding in the preceding clause. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The observed genotype effects in ArcAβ mice are attributable to cerebral amyloidosis or APP overexpression rather than to other genetic or developmental differences.

  • May combine two claims.

    Premisecitation

    Default mode network connectivity was reported affected in subjects at risk of developing Alzheimer's disease, including patients with mild cognitive impairment, cognitively healthy elders with amyloid deposits, and midlife carriers of the APOE4 risk allele.

    “Additionally, DMN connectivity was reported affected in subjects at risk of developing AD including patients with mild cognitive impairment (Rombouts et al., 2005;Sorg et al., 2007), in cognitively healthy elders with amyloid deposits (Hedden et al., 2009;Sperling et al., 2009;Sheline et al., 2010b), and in midlife carriers of APO ␧4 risk allele (Sheline et al., 2010a;Canuet et al., 2012).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Rombouts et al., 2005 source

      The Abstract and Discussion report altered default mode network deactivation in patients with mild cognitive impairment compared with healthy controls. But the study measured task-related deactivation, not connectivity directly; the Discussion's mention of altered resting connectivity concerns AD and cites another study. The other risk groups in the citing sentence have separate citations and are not attributed to Rombouts et al. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Sorg et al., 2007 source

      Not checked in the free run.

    • cites Hedden et al., 2009 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Alzheimer's disease often involves amyloid deposition around the vasculature.

    “Alzheimer's disease often involves amyloid deposition around the vasculature (Weller et al., 1998)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Weller et al., 1998 source

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

    Premisecitation

    Aβ peptides in various forms have been linked to alterations in cerebral calcium homeostasis, axonal guidance, axonal transport, and/or synaptic signaling.

    “A␤ peptides in various forms have been linked to alterations in cerebral calcium homeostasis (Kuchibhotla et al., 2008), axonal guidance (Cao et al., 2012), axonal transport, and/or synaptic signaling (Knobloch et al., 2007a), processes that ultimately might translate into impaired neural function.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Kuchibhotla et al., 2008 source
    • cites Cao et al., 2012 source
    • cites Knobloch et al., 2007a

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

  • May combine two claims.

    Premisecitation

    The ArcAβ mice show reduced synaptic plasticity and amyloid pathology affecting both the brain parenchyma and vasculature by 6 months of age.

    “The mice show reduced synaptic plasticity (Knobloch et al., 2007a), and amyloid pathology affecting both the brain parenchyma and vasculature by 6 months of age (Knobloch et al., 2007b;Merlini et al., 2011).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Knobloch et al., 2007a

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

    • cites Knobloch et al., 2007b

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

    • cites Merlini et al., 2011 source

  • May combine two claims.

    Premisecitation

    The ArcAβ model displays vascular pathology at a young age, leading in old animals to cerebral microbleeds, impaired vascular reactivity, and vascular remodeling.

    “The ArcA␤ model displays vascular pathology at a young age (Merlini et al., 2011) leading in old animals to cerebral microbleeds (Klohs et al., 2011), impaired vascular reactivity (Princz-Kranz et al., 2010), and vascular remodeling (Klohs et al., 2012).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Merlini et al., 2011 source
    • cites Klohs et al., 2011 source
    • cites Princz-Kranz et al., 2010 source

  • May combine two claims.

    Premisecitation

    Amyloid deposition around the vasculature affects neurovascular coupling and potentially masks functional connectivity measured by hemodynamic readouts such as BOLD fMRI and intrinsic optical imaging.

    “which inherently affects the neurovascular coupling and potentially masks FC measured on the basis of hemodynamic readouts, such as BOLD fMRI (Nicolakakis and Hamel, 2011) and intrinsic optical imaging (Bero et al., 2012).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Nicolakakis and Hamel, 2011 source
    • cites Bero et al., 2012 source

  • Classified as probably not a substantial claim.

    Premisecitation

    In Alzheimer's disease, plaque deposits, fibrils, and oligomers of Aβ are considered essential mediators in the pathophysiological cascade leading to cognitive decline.

    “In AD, plaque deposits, fibrils, and oligomers of A␤ are considered essential mediators in the pathophysiological cascade leading to cognitive decline (Mucke and Selkoe, 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mucke and Selkoe, 2012 source

      In the section on monomers, oligomers, and fibrils (page not provided), the paper links Aβ accumulation and soluble oligomers to neuronal dysfunction relevant to cognitive decline, and allows that plaques may have local neurotoxic effects. It does not treat plaques, fibrils, and oligomers alike as essential mediators: it describes insoluble fibrils as potentially relatively inactive reservoirs and reports that washed plaque cores did not block synaptic plasticity unless dissolved to release oligomers. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Only anecdotal parenchymal plaques were detected in brains of 5-month-old ArcAβ mice, whereas amyloid pathology was densely present in the cortex and hippocampus in 11- and 21-month-old animals.

    “Although only anecdotal parenchymal plaques have been detected in brains of 5 months old ArcA␤ mice, amyloid pathology was densely present in the cortex and hippocampus in 11-and 21-month-old animals (Fig. 7a).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The fractional surface occupied by amyloid plaques in the cortex is a valid measure of amyloid burden relevant to functional connectivity changes.

  • May combine two claims.

    Findingown data

    The genotype contrast for the 1-5 month and 5-19 month intervals indicated overall statistically significant differences across cortical ROIs between wild-type and ArcAβ mice during the 5-19 month interval, but only marginal difference during the 1-5 month interval.

    “The genotype contrast for the 1-5 month and 5-19 month interval indicated overall statistical significant differences across cortical ROIs between wild-type and ArcA␤ mice during the 5-19 months interval, but only marginal difference during the 1-5 months interval (Fig. 4d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.
    • Rests on an assumption: The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

  • May combine two claims.

    Findingown data

    ROI analysis illustrates a difference in fractional anisotropy in the anterior external capsule in both wild-type and transgenic mice (genotype effect p = 1.6 × 10−3, age effect p = 1.7 × 10−7), but not in the posterior external capsule.

    “ROI analysis illustrates the difference in FA in the anterior external capsule in both wild-type and transgenic mice (Fig. 6f; genotype effect: p ϭ 1.6 ϫ 10 Ϫ3 , age effect: p ϭ 1.7 ϫ 10 Ϫ7 ), but not in the posterior external capsule (Fig. 6g).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.
    • Rests on an assumption: The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

  • May combine two claims.

    Findingown data

    The rate of change of the correlation value per month was reduced for several cortical ROIs in ArcAβ compared with wild-type mice during the 1-5 month period, but not during the 5-19 month interval.

    “The rate of change of the correlation value per month (⌬Correlation/month) was evaluated using linear regression for the 1-5 month (Fig. 4a) and 5-19 month intervals (Fig. 4b), respectively, and displayed reduced rates for several cortical ROIs in ArcA␤ compared with wild-type mice during the 1-5 month period, but not during the 5-19 month interval (Fig. 4c).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.
    • Rests on an assumption: The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

  • May combine two claims.

    Findingown data

    In wild-type mice, the hippocampus displayed weak correlations with coefficients z ≤ 0.5 bilaterally and z ≤ 0.1 with other regions.

    “The hippocampus (Figs. 2, 3e) displayed weak correlations with coefficients z Յ 0.5 bilaterally, and z Յ 0.1 with other regions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.
    • Rests on an assumption: The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

  • May combine two claims.

    Findingown data

    Post hoc contrast analysis reveals differences in correlation between the parietal cortices during the 5-19 month interval, but only marginal differences during the 1-5 month period.

    “Post hoc contrast analysis of differences between ArcA␤ and wild-type between 1 and 5 months (bottom, left corner) and between 5 and 19 (top, right corner) reveals differences in correlation between the parietal cortices during the 5-19 month interval, but only marginal differences during the 1-5 month period.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rate difference reveals marked differences between ArcAβ and wild-type in Δcorrelation/month rates in the 1-5 months period in the anterior, medial and posterior parietal cortex, and marginal differences in rates during the 5-19 month interval.

    “The rate difference (c) reveals marked differences between ArcA␤ and wild-type in ⌬correlation/ month rates in the 1-5 months period in the anterior, medial and posterior parietal cortex, and marginal differences in rates during the 5-19 month interval.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    The diagnostic value of functional connectivity readout is hampered by poor reproducibility at the individual level.

    “however, the diagnostic value of this readout is hampered by poor reproducibility at the individual level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Effects on functional connectivity are paralleled by structural changes as derived from analysis of the fractional anisotropy of water diffusion, and occur in the early amyloid plaque buildup stage.

    “Effects on FC are paralleled by structural changes as derived from analysis of the FA of water diffusion, and occur in the early amyloid plaque buildup stage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ROI analysis shows the maximum fractional anisotropy value along a line profile across the anterior external capsule (genotype effect: p = 1.3 × 10−3) and posterior external capsule.

    “ROI analysis shows the maximum FA value along a line profile across the anterior external capsule (ROI ec ant , f; genotype effect: p ϭ 1.3 ϫ 10 Ϫ3 ) and posterior external capsule (ROI ec post , g)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A genotype × interaction effect was observed in the anterior and posterior parietal cortex bilateral correlation, left-to-right motor cortex pair, and retrosplenial/cingulate cortex.

    “Genotype ϫ interaction effect was observed in the anterior and posterior parietal cortex bilateral correlation (a, p ϭ 2.5 ϫ 10 Ϫ8 ; b, p ϭ 5.5 ϫ 10 Ϫ3 ), left-to-right motor cortex pair (c, p ϭ 2.4 ϫ 10 Ϫ4 ), and retrosplenial/cingulate cortex (d, p ϭ 1.3 ϫ 10 Ϫ2 ,).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunohistological detection reveals sparse amyloid plaques at 5 months with increasing plaque load at 11 and 21 months in ArcAβ transgenic mice.

    “Immunohistological detection of A␤ peptides ArcA␤ transgenic mice at 2, 5, 11, and 21 months, and wild-type control reveal sparse amyloid plaques at 5 months with increasing plaque load at 11 and 21 months (a).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A linear mixed model analysis was performed with gender, age, genotype, and their twofold interactions as fixed effects.

    “A linear mixed model analysis was performed with gender, age, genotype, and their twofold interactions as fixed effects using lme4 package.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Studies addressing the implication of amyloid pathology on brain functional connectivity in animals are lacking because fMRI in mice is challenging.

    “Although the molecular processes underlying amyloid pathology in animals have been examined extensively, studies addressing its implication on brain FC are lacking as fMRI in mice is challenging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The marginal decline in FC in ArcAβ mice between 5 and 21 months is consistent with the dissociation between amyloid load and connectivity.

    “consistent with the dissociation between amyloid load and connectivity (Adriaanse et al., 2014)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Adriaanse et al., 2014

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

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

    Study design and conductnone given

    All animals measured were included in the analysis.

    “All animals measured were included in the analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Diffusion tensor imaging in the APP/PS1 model revealed a fractional anisotropy difference map overlapping with our results, including increased FA in the minor forceps.

    “Diffusion tensor imaging in the APP/PS1 model revealed a FA difference map overlapping with our results, including increased FA in the minor forceps (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). May combine two claims.

    Study design and conductown data

    Preprocessing EPI image deformation induced by magnetic field inhomogeneity was minimal in most scans and was accounted for by the nonlinear transformation during coregistration.

    “Preprocessing EPI image deformation induced by the magnetic field inhomogeneity was minimal in most scans and was accounted for by the nonlinear transformation during the coregistration.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Medial parietal cortex bilateral correlation yielded a test-retest correlation of r = 0.48.

    “For example medial parietal cortex bilateral correlation yielded a test-retest correlation of r ϭ 0.48 (Fig. 8b).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A test-retest correlation of r = 0.4–0.58 is sufficient reliability for functional connectivity analysis.

  • Classified as probably not a substantial claim.

    Premisenone given

    The ArcAβ transgenic mouse model of cerebral amyloidosis overexpresses the human APP protein with the Swedish and Arctic mutations.

    “The ArcA␤ transgenic mouse model of cerebral amyloidosis has been used, which overexpresses the human APP protein with the Swedish and Arctic mutations.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Animal models of amyloid pathology offer an experimental platform for studying Alzheimer's disease.

    “Animal models of amyloid pathology offer an experimental platform to studying AD (Gordon et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gordon et al., 2002 source

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

    Study design and conductown data

    Residual analysis of the mixed models was performed on randomly selected samples (n = 30) with QQ-plots, Tukey-Anscombe plots, and scale location plots, and the assumption of normally distributed residuals was considered plausible in all tested fractional anisotropy samples and in all randomly tested functional connectivity pairs describing cortical interactions.

    “Residual analysis of the mixed models was performed on randomly selected samples (n ϭ 30) with QQ-plots to inspect normal distribution, Tukey-Anscombe plots for the homogeneity of the variance and skewness, and scale location plots for homoscedasticity (i.e., the homogeneity of residual variance).The assumption of normally distributed residuals was considered plausible in all tested fractional”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Multiple comparison was corrected with false discovery rate, with q = 0.05 for network comparison and q = 0.15 for voxelwise analysis.

    “Multiple comparison was corrected with false discovery rate (FDR) (Benjamini and Hochberg, 1995), with q ϭ 0.05 for network comparison, and q ϭ 0.15 for voxelwise analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Benjamini and Hochberg, 1995 source

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

    Study design and conductown data

    Temporal signal-to-noise ratio in the somatosensory cortex varied between functional imaging sessions, with animals imaged at 2 and 21 months of age displaying the highest tSNR values.

    “Temporal signal-to-noise ratio (tSNR) in the somatosensory cortex was found to vary between functional imaging sessions (Table 1; Fig. 8c) with animals imaged at 2 and 21 months of age displaying the highest tSNR values.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Fractional anisotropy of the external capsule showed test-retest values of r = 0.39.

    “In comparison, fractional anisotropy of the external capsule showed similar testretest values of r ϭ 0.39.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A test-retest correlation of r = 0.4–0.58 is sufficient reliability for functional connectivity analysis.

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

    Premisecitation

    A significant fraction of Alzheimer's disease patients is affected by severe vasculopathy.

    “as a significant fraction of these patients is affected by severe vasculopathy (Castellani et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellani et al., 2004 source

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

    Study design and conductnone given

    All animal experiments in this study were performed in adherence to the Swiss law of Animal Protection and were approved by the Zurich cantonal veterinary office.

    “All animal experiments in this study have been performed in adherence to the Swiss law of Animal Protection and were approve by the Zurich cantonal veterinary office.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    Given the large phenotypic variations between mouse models of Alzheimer's disease, different functional connectivity patterns and dynamics are to be expected.

    “Yet, given the large phenotypic variations between mouse models of AD (Balducci and Forloni, 2011), different FC patterns and dynamics are to be expected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Balducci and Forloni, 2011 source

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

    Study design and conductown data

    There was no apparent difference related to coregistration in the mean images in the individual groups.

    “There was no apparent difference related to coregistration in the mean images in the individual groups as illustrated with 1-and 11-monthold animals (Fig. 1a,b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Development of functional connectivity in the somatosensory and motor cortex, as derived from temporal correlation of rs-fMRI signals, occurs during the first months of life in wild-type mice and appears significantly impaired in age-matched ArcAβ mice.

    “Development of FC in the somatosensory and motor cortex, as derived from the temporal correlation of rs-fMRI signals, occurs during the first months of life in wild-type mice and appears to be significantly impaired in age-matched ArcA␤ mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.
    • Rests on an assumption: The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

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

    Premisenone given

    Isoflurane has been shown to reveal predominantly cortical correlations, whereas medetomidine favored the detection of subcortical correlations.

    “We have used isoflurane as an anesthetic, which has been shown to reveal predominantly cortical correlations, whereas medetomidine favored the detection of subcortical correlations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The major finding of the study is early and robust functional changes occurring in ArcAβ transgenic mice, appearing before amyloid deposition as derived from histological analysis and reported earlier for this animal model.

    “The major finding of our study relates to the early and robust functional changes occurring in ArcA␤ transgenic mice, appearing before amyloid deposition as derived from histological analysis and reported earlier for this animal model (Knobloch et al., 2007b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Knobloch et al., 2007b

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

    • Rests on an assumption: The observed genotype effects in ArcAβ mice are attributable to cerebral amyloidosis or APP overexpression rather than to other genetic or developmental differences.
    • Rests on an assumption: The fractional surface occupied by amyloid plaques in the cortex is a valid measure of amyloid burden relevant to functional connectivity changes.

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

    Study design and conductown data

    Anesthesia resulted in breathing rates of 120 ± 15 breaths per minute.

    “Anesthesia resulted in breathing rates of 120 Ϯ 15 breaths per min.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Isoflurane levels were titrated to achieve animal sedation, with lower doses resulting in excessive motion artifacts.

    “We have titrated isoflurane levels to achieve animal sedation, with lower doses resulting in excessive motion artifacts.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Signal traces from regions of high temporal variance were regressed from the time series for every voxel along with motion parameters, which led to an effective reduction in variance.

    “The signal traces were then extracted from these regions and regressed from the time series for every voxel (to account for vascular contributions) along with the motion parameters, which led to an effective reduction in variance in region as indicated by the variance analysis (Fig. 1c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    There were no differences in temporal signal-to-noise ratio between wild-type and transgenic animals, or between male and female animals, at any time point.

    “There was no differences in tSNR between wild-type and transgenic animals, or male and females at any time point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Neither temporal signal-to-noise ratio nor motion showed a statistically significant effect in the linear mixed model analysis.

    “Finally, neither tSNR nor motion showed statistical significant effect in the linear mixed model analysis.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Fractional anisotropy evolution during the first months of life has been related to maturation of myelination in rats.

    “FA evolution during the first months of life has been related to maturation of myelination in rats (Mengler et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mengler et al., 2014

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

  • May combine two claims.

    Interpretationown data

    These functional deficits are observed before and during the early plaque build-up stage, although there was only marginal decline in functional connectivity after 5 months of age during amyloid plaque buildup.

    “These functional deficits are observed before and during the early plaque build-up stage, although there was only marginal decline in FC after 5 months of age during amyloid plaque buildup.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.
    • Rests on an assumption: The observed genotype effects in ArcAβ mice are attributable to cerebral amyloidosis or APP overexpression rather than to other genetic or developmental differences.
    • Rests on an assumption: The fractional surface occupied by amyloid plaques in the cortex is a valid measure of amyloid burden relevant to functional connectivity changes.

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

    Study design and conductown data

    No visible difference appears between the groups, suggesting the validity of the linear and nonlinear transformation applied.

    “No visible difference appears between the groups suggesting the validity of the linear and nonlinear transformation applied.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Voxelwise regression was performed with the signal extracted from these regions, leading to reduced variance in these regions.

    “Voxelwise regression was performed with the signal extracted from these regions, leading to reduced variance in these regions.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The tSNR is shown per age group and genotype, and indicates a peak at 2 and 21 months, with tSNR values ranging between 105 and 169.

    “The tSNR is shown per age group and genotype, and indicates a peak at 2 and 21 months, with tSNR values ranging between 105 and 169 (c).”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    Cross-sectional age differences in mice reflect longitudinal development of functional connectivity and white matter structure.

    “In this study, ArcA␤ transgenic and wild-type mice were imaged using resting-state fMRI methods across their life-span in a cross-sectional design to analyze changes in FC in relation to the pathology.”
    “We have assessed the FC in mice across their lifespan, from 1 to 21 months, in a cross-sectional design using rs-fMRI.”

  • The paper relies on this without support.

    The observed genotype effects in ArcAβ mice are attributable to cerebral amyloidosis or APP overexpression rather than to other genetic or developmental differences.

    “Our results suggest cerebral amyloidosis in mice is preceded by impairment of neuronal networks and white matter structures.”

  • The paper relies on this without support.

    Resting-state fMRI-derived functional connectivity in anesthetized mice measures neuronal network connectivity relevant to brain function.

    “Functional connectivity was measured as the Pearson correlation coefficient between mean time series from each brain region pairs, corrected with Fisher z-transformation for bounded values.”

  • The paper relies on this without support.

    The fractional surface occupied by amyloid plaques in the cortex is a valid measure of amyloid burden relevant to functional connectivity changes.

    “ROI analysis was performed in ImageJ (NIH) to estimate the fractional surface occupied by amyloid plaques by delineating the cortical regions according to the atlas used for the FC analysis.”

  • The paper relies on this without support.

    If amyloid plaques caused functional connectivity changes, a correlation between plaque surface and functional connectivity would be detectable.

    “There was however no correlation between the surfaces occupied by amyloid plaques and bilateral correlation between the corresponding areas (Fig. 7c; r ϭ 0.08).”

  • The paper relies on this without support.

    Early functional connectivity and fractional anisotropy changes in ArcAβ mice are relevant to human Alzheimer's disease.

    “The results compare well with growing evidence of early functional impairments in humans at risk of developing Alzheimer's disease, such as mid-life APO␧4 carriers (Sheline et al., 2010a;Canuet et al., 2012) or asymptomatic elderly with amyloid deposition (Hedden et al., 2009;Sperling et al., 2009;Sheline et al., 2010b), and corroborate the reported absence of a correlation between amyloid plaques”

  • The paper relies on this without support.

    The in-house atlas template with 24 ROIs accurately represents the functional organization of the mouse brain.

    “Mean time series were extracted from the regressed images using an in-house atlas template based on the functional organization of the mouse brain with 24 different ROIs (Fig. 1d).”

  • The paper relies on this without support.

    A test-retest correlation of r = 0.4–0.58 is sufficient reliability for functional connectivity analysis.

    “Variance of the within-subject effect was lower than the residual variance by two orders of magnitude, which is corroborated with a relatively low correlation in test-retest analysis ranging between r ϭ 0.4 and r ϭ 0.58 across cortical pairwise correlations (Fig. 8a).”

  • The paper relies on this without support.

    Isoflurane anesthesia does not differentially affect functional connectivity in ArcAβ transgenic mice compared with wild-type mice.

    “All anesthetics interact with neurotransmitter systems, which might be affected in a differential way in different mouse lines.”
    “Hence, isoflurane anesthesia may exacerbate the effects of amyloidosis in fMRI studies in these animals.”

  • The paper relies on this without support.

    All anesthetics interact with neurotransmitter systems, which might be affected in a differential way in different mouse lines.

    “All anesthetics interact with neurotransmitter systems, which might be affected in a differential way in different mouse lines.”

  • The authors state this as an assumption.

    Interference by anesthesia is a potential confound in the study of functional connectivity in rodents.

    “A potential confound in the study of FC in rodents is interference by anesthesia.”
11 of 11

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?

  • Aβ load at 6 months is low in TG mice compared to 11 months.

    “The Ab load at 6 months is low in TG mice compared to 11 months (Grandjean et al., 2014).”

    From Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis (2020) · cites this paper as Grandjean et al., 2014

    The section “Amyloid plaque deposition starts in the early life stage” reports only anecdotal plaques at 5 months, compared with dense pathology at 11 months. This supports the age-related comparison, but the paper does not report Aβ load at the claimed age of 6 months. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Previous studies of APP/PS1 and ArcBeta transgenic mice have demonstrated deficits in the functional connectivity of multiple brain regions that is associated with amyloid deposition.

    “Previous studies of APP/PS1 and ArcBeta transgenic mice have demonstrated deficits in the functional connectivity of multiple brain regions that is associated with amyloid deposition (Bero et al., 2012; Grandjean et al., 2014; Shah et al., 2013).”

    From Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer’s disease (2018) · cites this paper as Grandjean et al., 2014

    The Discussion reports reduced functional connectivity in ArcAβ mice, particularly early in life, so the deficit portion is supported. But those changes appeared before amyloid deposition, and the paper says it could not correlate them with plaque burden. The cited paper discusses APP/PS1 findings from another study rather than demonstrating APP/PS1 deficits itself. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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

    “DTI shows sensitivity to axon and myelin pathology, where breakdown of white matter integrity results in measurable differences in diffusion of water molecules [15,16].”

    From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [15]

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

    Experimental — accuracy not yet measured

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.

  • Different genotype-effect p values for the same FA plot

    Minor

    The Results and Figure 6 caption give different genotype-effect p values for the anterior external capsule analysis in Figure 6f.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Grandjean, J., Schroeter, A., He, P., Tanadini, M., Keist, R., Krstic, D., Konietzko, U., Klohs, J., Nitsch, R. M., & Rudin, M.
Affiliations
  • ETH Zurich (CH)
  • Institute for Biomedical Engineering (CH)
  • University of Zurich (CH)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2014-10-08
Volume
34
Issue
41
Pages
13780-13789
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.4762-13.2014
PMC
PMC6608375
OpenAlex
W1969125278
Semantic Scholar
a93f9b04c7cf2afc40cbbfccc5312b0c266bd66a
Cited by
70
References
43
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 9 · 2019: 9 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 6
FWCI
3.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • PubMed Central (submittedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-sa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • ETH Zürich Research Collection
  • Zurich Open Repository and Archive (University of Zurich)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (141202, 310030, 126029)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
cerebral amyloidosis, functional connectivity, white matter, amyloid precursor protein, Alzheimer's disease, amyloid plaques, resting-state fMRI, diffusion tensor imaging, fractional anisotropy, sensorimotor cortex, postnatal development, neuronal networks
MeSH terms
Aging, Alzheimer Disease, Amyloidosis, Animals, Female, Genotype, Humans, Male, Mice, Transgenic, Nerve Net, Neural Pathways, Anisotropy, Mice, White Matter

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 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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 ›

Are you an author, or do you see a problem with this page? Request a review