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PreprintCited by 2Advanced Neuroimaging Techniques and ApplicationsAlzheimer's disease research and treatmentsFunctional Brain Connectivity Studies

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

Open access
Al-Amin, Md. Mamun, Grandjean, Joanes, Klohs, Jan, Kim, Jungsu·2020·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2020.04.27.064634
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Abstract

Although amyloid beta (Aβ) deposition is one of the major causes of white matter (WM) alterations in Alzheimer’s disease (AD), little is known about the underlying basis of WM damage and its association with global structural connectivity and network topology. We aimed to dissect the contributions of WM microstructure to structural connectivity and network properties in the ArcAβ mice model of Aβ amyloidosis. We acquired diffusion-weighted images (DWI) of wild type (WT) and ArcAβ transgenic (TG) mice using a 9.4 T MRI scanner. Fixel-based analysis (FBA) was performed to measure fiber tract-specific properties. We also performed three complementary experiments; to identify the global differences in structural connectivity, to compute network properties and to measure cellular basis of white matter alterations. Transgenic mice displayed disrupted structural connectivity centered to the entorhinal cortex (EC) and a lower fiber density and fiber bundle cross-section. In addition, there was a reduced network efficiency and degree centrality in weighted structural connectivity in the transgenic mice. To further examine the underlying neuronal basis of connectivity and network deficits, we performed histology experiments. We found no alteration in myelination and an increased level of neurofilament light (NFL) in the brain regions with disrupted connectivity in the TG mice. Furthermore, TG mice had a reduced number of perineuronal nets (PNN) in the EC. The observed FDC reductions may indicate a decrease in axonal diameter or axon count which would explain the basis of connectivity deficits and reduced network efficiency in TG mice. The increase in NFL suggests a breakdown of axonal integrity, which would reduce WM fiber health. Considering the pivotal role of the EC in AD, Aβ deposition may primarily increase NFL release, damaging PNN in the entorhinal pathway, resulting in disrupted structural connectivity.

AI snapshot

Written from the paper’s full text.

TL;DR

In the ArcAβ mouse model of Aβ amyloidosis, transgenic mice showed disrupted white matter fiber-specific properties and structural connectivity centered on the entorhinal cortex, alongside reduced network efficiency and degree centrality. Histology linked these connectivity deficits to increased neurofilament light and reduced perineuronal nets, without evidence of altered myelination.

Key findings

  • Fixel-based analysis found significant (FWE-corrected p ≤ 0.05) reductions in fiber density (FD), fiber bundle cross-section (FC), and fiber density plus cross-section (FDC) in transgenic mice, mainly in the right hemisphere: corpus callosum, hippocampal commissure, retrosplenial cortex, dorsal hippocampus, and thalamus.
  • Network-based statistics identified disrupted structural connectivity in five right-hemisphere nodes—entorhinal cortex (EC.R), periaqueductal grey (Pag.R), subiculum (Sub.R), mediolateral cortex (V2ml.R), and secondary visual cortex (V2.R)—with the lowest p-values at threshold t = 3.4 for network intensity (p = 0.029) and extent (p = 0.048); the EC was the largest module with 3 edges.
  • Graph theory showed reduced degree centrality (t13 = 2.21, p = 0.045) and local efficiency (t13 = 2.26, p = 0.041) in transgenic mice, while betweenness centrality, global efficiency, small-world clustering coefficient, small-world path length, nodal clustering coefficient, and nodal shortest path length were not significantly reduced.
  • Immunohistochemistry showed increased NFL immunoreactivity in transgenic mice across brain regions (main effect of genotype F1,162 = 131.7, p < 0.001; genotype × ROI interaction F4,162 = 10.31, p < 0.001), no significant genotype × ROI interaction for MBP, and reduced PNN intensity in EC, V2, and V2ml; PNN count was reduced in EC and V2 but not hippocampus.

Methods

  • A total of 32 mice were used: diffusion MRI in WT (n = 12) and ArcAβ transgenic (n = 8) mice aged 381–431 days, plus an additional 12 mice (n = 6/group) aged 157–214 days for immunohistochemistry.
  • DWI was acquired on a 9.4 T Bruker scanner with voxel size 0.15 × 0.13 × 0.45 mm, TR = 2000 ms, TE = 22 ms, b = 0 and 1000 s/mm², and 36 directions; analyses included fixel-based analysis, probabilistic tractography, 76-region structural connectomes, network-based statistics with 5000 permutations, and graph theory using GRETNA.
  • Immunohistochemistry labeled NFL, myelin basic protein (MBP), and perineuronal nets (PNN) with WFA; two-way ANOVA followed by Bonferroni post hoc tests compared genotype and brain region effects.

Limitations

  • The authors state they could not include the MRI brain samples in histology because those samples were exhausted in a previous study.
  • The authors note the DWI voxel size was 0.15 × 0.13 × 0.45 mm, so crossing-fiber calculation may not have been realistic, especially with a 0.45 mm slice; they argue this was mitigated by probabilistic tractography and 36 diffusion directions.
  • The authors did not measure myelin proteolipid protein (MPP) or myelin oligodendrocyte glycoprotein (MOG), and they did not measure pre- or post-synaptic density; evident from the text, the sample sizes were small (n = 8 transgenic for MRI, n = 6/group for histology) and the MRI and histology cohorts differed in age.

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

Integrity signals

Registry

Crossref · 10.1101/2020.04.27.064634

Cites

102 of 102 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

28 of 51 cited sources checked · 15 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    Decreased local and global efficiency is a common characteristic of patients with AD.

    “A decreased local (Zhou and Lui, 2013) and global (Martensson et al., 2018) efficiency is a common characteristic of patients with AD.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Zhou and Lui, 2013 source
    • cites Martensson et al., 2018 source

      The citation to Mårtensson et al. is attached to global efficiency, not local efficiency. The Results report significantly increased global efficiency in AD patients for binary networks generated from cortical thickness, and the Discussion reports a stable, significant increase—not the claimed decrease. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Aβ mouse model of amyloidosis (5XFAD mice) also showed a decreased network efficiency.

    “In addition, Aβ mouse model of amyloidosis (5XFAD mice) also showed a decreased network efficiency (Kesler et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kesler et al., 2018 source

      The Discussion explicitly says that decreased network efficiency, reported in patients with AD, was not observed in the 5XFAD mice. The paper reports other connectome differences, including higher characteristic path length, but does not equate those findings with decreased efficiency. (LLM, conf=0.95)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Existing evidence from human studies strongly supports the relationship between raised NFL levels and WM microstructure damage.

    “Existing evidence from human studies strongly support the relationship between raised NFL levels and WM microstructure damage (Moore et al., 2018, Osborn et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Moore et al., 2018 source
    • cites Osborn et al., 2018 source

      The Discussion (page unavailable) reports that higher CSF NFL was associated with greater white matter hyperintensities in older adults. This supports a relationship with white matter injury, but the study measured FLAIR-assessed hyperintensities, not white matter microstructure directly, and describes its cross-sectional findings as initial evidence rather than strong support. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Amyloid deposition damages the ECM scaffold.

    “Amyloid deposition damages the ECM scaffold (Ajmo et al., 2010, Sykova et al., 2005).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Ajmo et al., 2010 source

      The Discussion (page not supplied) says Aβ deposition may disrupt ECM processing, and reports altered processing of the ECM component brevican in plaque-bearing mice. It does not establish that amyloid deposition directly damages the ECM scaffold; the authors leave the mechanism and broader effects uncertain. (LLM, conf=0.84)

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

      The Discussion links possible loss of extracellular matrix molecules to aging in control mice, and separately describes amyloid plaques and altered extracellular-space properties in APP23 mice. The passages searched do not say that amyloid deposition damages the extracellular matrix scaffold. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation

    Disrupted structural connectivity in the EC is also a feature of AD.

    “Disrupted structural connectivity in the EC is also a feature of AD (Mallio et al., 2015).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mallio et al., 2015 source
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 17

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

    Premisecitation

    Aβ plaque deposition and impaired cognitive function begin at 6 months, with vascular Aβ appearing between 9 and 15 months.

    “Aβ plaque deposition and impaired cognitive function begins at 6 months (Knobloch et al., 2007b), with vascular Aβ appearing between 9 and 15 months (Merlini et al., 2011).”
    Quote in the paperNot a substantial claim1 of 2 sources 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

      The citation to Merlini et al. is attached to the claim that vascular Aβ appears between 9 and 15 months, not to the preceding claim about plaques and cognition. The Results (Fig. 4) report vascular Aβ deposits already at the early stage, which the Methods define as 6 months old. The deposits were few at that age, but they had appeared before 9 months. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    EC provides output to the subiculum, while receives inputs from the sensory cortex including the visual cortex.

    “EC provide output to the subiculum ( O'Mara, 2005), while receives inputs from the sensory cortex including the visual cortex (Kerr et al., 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites O'Mara, 2005 source
    • cites Kerr et al., 2007 source

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

    Premisecitation

    EC and hippocampus are two key vulnerable brain regions in AD, becoming affected in the early stages of AD.

    “The EC and hippocampus are two key vulnerable brain regions in AD, becoming affected in the early stages of AD (Mak et al., 2017, Hett et al., 2019).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Mak et al., 2017 source

      The Results and Discussion report hippocampal atrophy in both AD and MCI, and the Discussion says tau accumulates early in the hippocampus. The Discussion mentions the entorhinal cortex only as connected to hippocampal CA1; it does not say that the entorhinal cortex is affected early in AD. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Hett et al., 2019 source

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

    Premisecitation

    Several studies describe an association between cognitive impairment and increased CSF and plasma NFL in AD.

    “Furthermore, several studies describe association between cognitive impairment and increased CSF (Zetterberg et al., 2016) and plasma NFL (Lin et al., 2018) in AD.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Zetterberg et al., 2016 source
    • cites Lin et al., 2018 source

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

    Premisecitation

    The brain's extracellular matrix plays a potential role in maintaining connectivity in brain networks.

    “Besides the role of myelin and NFL, the brain's extracellular matrix (ECM) plays a potential role in maintaining the connectivity in brain networks (Bikbaev et al., 2015).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bikbaev et al., 2015 source

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

    Premisecitation

    PNN envelop the soma, stabilizing interneuron activity, regulating synaptic homeostasis and protecting interneurons from oxidative damage.

    “This lattice-like structure envelop the soma, stabilizing interneuron activity, regulating synaptic homeostasis (Bosiacki et al., 2019) and protecting interneurons from oxidative damage (Morawski et al., 2004).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Bosiacki et al., 2019 source

      The Introduction says PNNs surround cell bodies, occur especially around parvalbumin interneurons, and are important for their activity. Section 6 describes how PNNs control synaptic connections and receptor mobility, supporting a role in synaptic homeostasis. The copy does not specifically say they stabilize interneuron activity. Oxidative protection is attributed to Morawski et al. in the citing sentence, not to this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Morawski et al., 2004 source

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

    Premisecitation

    Aβ peptide is cytotoxic to oligodendrocyte cells, acting through sphingomyelinase-ceramide signaling.

    “Ab peptide is cytotoxic to oligodendrocyte cells, acting through sphingomyelinase-ceramide signaling (Lee et al., 2004).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Lee et al., 2004 source

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

    Premisecitation

    Perineuronal nets (PNN) regulate synaptic plasticity and rewiring of the network of interneurons.

    “Importantly, PNN regulate the synaptic plasticity (Kochlamazashvili et al., 2010) and rewiring the network (Pollock et al., 2014) of the interneurons (Wen et al., 2018).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Kochlamazashvili et al., 2010 source
    • cites Pollock et al., 2014 source
    • cites Wen et al., 2018 source

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

    Premisecitation

    Neurons with intact PNN never deposit neurofibrillary tangles.

    “neurons having intact PNN never deposits neurofibrillary tangles (Morawski et al., 2012)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Morawski et al., 2012 source

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

    Premisecitation

    PNN has an indirect role over principal neurons via regulating synaptic plasticity and dendritic arborization of the interneuron.

    “PNN has an indirect role over principal neurons via regulating synaptic plasticity (Sigal et al., 2019) and dendritic arborization (Stolp et al., 2019) of the interneuron.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Sigal et al., 2019 source
    • cites Stolp et al., 2019 source

      The Discussion suggests that changes involving perineuronal nets and parvalbumin interneurons may affect pyramidal-neuron function indirectly. But Stolp et al. do not show that perineuronal nets regulate interneuron dendritic arborization; the Results report no significant difference in the dendritic arborization of the cortical neurons examined at P40. The Stolp citation is attached specifically to the arborization part of the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    There is inconsistency in PNN findings in transgenic mouse models of Alzheimer's disease.

    “There is some inconsistency on PNN findings in the transgenic mouse model of AD.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Yang et al., 2015 source

      The Introduction describes a P301S tau transgenic mouse model, and the Results discuss PNN manipulation, but neither compares PNN findings across Alzheimer's disease mouse models. Searches for inconsistent, conflicting, increased, and decreased PNN findings found no passage addressing the claimed inconsistency. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites Morawski et al., 2010b

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

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

    Premisecitation

    The vulnerability of entorhinal neurons has been reported in previous studies.

    “The vulnerability of the entorhinal neurons has been reported in many previous studies (Adams et al., 2019, Rodriguez et al., 2019, Braak and Del Tredici, 2020).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Adams et al., 2019 source
    • cites Rodriguez et al., 2019

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

    • cites Braak and Del Tredici, 2020 source

  • May combine two claims.

    Findingown data

    There was a main effect of Genotype and ROI but not interaction on total number of PNN cells.

    “We further analyzed WFA-labelled PNN cells and found a main effect of Genotype (F 1,167 = 24.89;p < 0.001) and ROI (F 4,167 = 59.14; p < 0.001) but not interaction (F 4,167 = 1.77; p < 0.136) on total number of PNN cells (Fig. 6e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was a significant main effect of Genotype and ROI on MBP intensity, but no significant interaction between Genotype and ROI.

    “Further two-way (Genotype x ROI) ANOVA analysis on MBP intensity showed a significant main effect of Genotype (F1,164 = 9.57; p < 0.005) and a significant main effect of ROI (F4,164 = 304.8;p < 0.001).However, there was no significant interaction (F4,162 = 1.91; p = 0.111) between Genotype with ROI (Fig. 5d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Here, we observed reduced local and global efficiency and degree centrality.

    “Here, we observed reduced local and global efficiency and degree centrality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transgenic mice had lower fiber density and fiber bundle cross-section.

    “Transgenic mice displayed disrupted structural connectivity centered to the entorhinal cortex (EC) and a lower fiber density and fiber bundle cross-section.”
    • Also stated in: § Discussion · boosted
      “Our results of whole-brain fixel-based analysis demonstrated a reduced fiber density and fiber cross-section in the ArcAβ transgenic mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transgenic ArcAβ mice display a reduction in fiber density plus fiber bundle cross-section (FDC).

    “Transgenic mice display a reduction in fiber density (FD) (row A), fiber bundle cross-section (FC) (row B), and fiber density plus fiber bundle cross-section (FDC) (row C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The increase in NFL suggests a breakdown of axonal integrity, which would reduce WM fiber health.

    “The increase in NFL suggests a breakdown of axonal integrity, which would reduce WM fiber health.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Since FDC is reduced in TG mice, both a reduction in axons and a reduction in cross-sectional area are possible.

    “Since we show that fiber density plus bundle cross section is reduced in TG mice, both are possible.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Decreased fiber properties indicates a reduction in axons within a particular fiber bundle or a decreased intra-axonal volume of fibers.

    “Decreased fiber properties indicates a reduction in axons within a particular fiber bundle or a decreased intra-axonal volume of fibers.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    NFL is a potential biomarker of WM damage.

    “Since NFL is a potential biomarker of WM damage (Sjogren et al., 2001), we hypothesized that the levels of NFL would increase in mouse model of Aβ amyloidosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sjogren et al., 2001 source

  • May combine two claims.

    Interpretationreasoning

    Aβ deposition may primarily increase NFL release, damaging PNN in the entorhinal pathway, resulting in disrupted structural connectivity.

    “Considering the pivotal role of the EC in AD, Aβ deposition may primarily increase NFL release, damaging PNN in the entorhinal pathway, resulting in disrupted structural connectivity.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    An alternative explanation is a reduction of the cross-sectional area of a fiber tract, resulting in smaller axonal diameter.

    “An alternative explanation is a reduction of the cross-sectional area of a fiber tract, resulting in smaller axonal diameter.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The observed FDC reductions may indicate a decrease in axonal diameter or axon count, which would explain the basis of connectivity deficits and reduced network efficiency in TG mice.

    “The observed FDC reductions may indicate a decrease in axonal diameter or axon count which would explain the basis of connectivity deficits and reduced network efficiency in TG mice.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The study was unable to include the MRI brain samples in the histology experiment because those brain samples were exhausted in a previous study.

    “This study has some limitations, mainly that we were unable to include the MRI brain samples in our histology experiment, as those brain samples were exhausted in a previous study (Grandjean et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grandjean et al., 2016 source

  • Classified as probably not a substantial claim.

    Premisecitation

    PNN prevents Aβ-induced neurotoxicity in cortical neurons.

    “PNN prevents Aβ-induced neurotoxicity in cortical neurons (Miyata et al., 2007)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miyata et al., 2007 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Streamlines were identified following Family wise error (FWE) correction at p < 0.05.

    “The streamlines were found following Family wise error (FWE) correction at p < 0.05 and overlaid on the AMBMC atlas (Ullmann et al., 2014).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The authors showed 10-1000-fold higher CSF NFL in these TG mice.

    “The authors showed 10-1000-fold higher CSF NFL in these TG mice, whereas, we found approximately 100-fold increase in NFL in ArcAb TG mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bacioglu et al., 2016 source

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

    Premisecitation

    A study on three different mouse models of neurodegenerative diseases showed increased plasma and CSF NFL with age.

    “Study on three different mouse models of neurodegenerative diseases (A53T-aS, P301S-Tau and APP/PS1) showed increased plasma and CSF NFL with age (Bacioglu et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bacioglu et al., 2016 source

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

    Study design and conductown data

    The study measured MBP expression but did not measure other myelin proteins such as myelin proteolipid protein (MPP) and myelin oligodendrocyte glycoprotein (MOG).

    “We measured the expression of MBP, but did not measure the expression of other myelin proteins, such as myelin proteolipid protein (MPP) and myelin oligodendrocyte glycoprotein (MOG).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    NFL gene deletion increased amyloid plaque load and synaptic pathology in APP/PS1 TG mice.

    “Surprisingly, NFL gene deletion increased amyloid plaque load and synaptic pathology in APP/PS1 TG mice (Fernandez-Martos et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fernandez-Martos et al., 2015 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The discrepancies in these findings could be partly because of the heterogeneous vulnerability of PNN to amyloid toxicity in distinct brain regions.

    “The discrepancies in these findings could be partly because of the heterogeneous vulnerability of PNN to amyloid toxicity in distinct brain regions, reinforcing the importance of considering specific brain regions in the study of Alzheimer's pathology.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The entorhinal cortex (EC) and hippocampus are the primary brain regions affected in the early stages of Alzheimer's disease.

  • Classified as probably not a substantial claim.

    Premisecitation

    Neurons with aggrecan-linked PNN protect against tau pathology.

    “neurons with aggrecan-linked PNN protect tau pathology (Morawski et al., 2010a)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morawski et al., 2010a

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

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

    Premisecitation

    Reduced PNN expression has been shown in Tg2576 mice.

    “Furthermore, reduced PNN expression had recently shown in Tg2576 mice (Cattaud et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cattaud et al., 2018 source
34 of 34

  • The paper relies on this without support.

    There is a lack of knowledge on whether fiber-specific WM properties are compromised in AD.

    “To date, there is a lack of knowledge on whether fiber-specific WM properties are compromised in AD.”

  • The paper relies on this without support.

    It is unclear whether structural connectivity is altered in the mouse model of Aβ amyloidosis.

    “In addition, it is less clear whether structural connectivity is altered in the mouse model of Aβ amyloidosis.”

  • The paper relies on this without support.

    None of the previous studies quantified NFL in axons and dendrites.

    “However, none of these studies quantified NFL in axons and dendrites.”

  • The paper relies on this without support.

    MBP is the major constituent of brain myelin and is synthesized by oligodendrocytes and Schwann cells.

    “MBP is the major constituent of brain myelin and is synthesized by oligodendrocyte and Schwann.”

  • The paper relies on this without support.

    The role of the entorhinal cortex (EC) in connectome deficits in mice has received less attention.

    “Although the EC has been widely studied for its critical role in AD, its role in connectome deficits in mice has received less attention.”

  • The paper relies on this without support.

    The entorhinal cortex (EC) and hippocampus are the primary brain regions affected in the early stages of Alzheimer's disease.

    “The EC and hippocampus are the primary brain regions that are affected in the early stages of AD.”
6 of 6

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.

  • No demyelination claim conflicts with reduced myelin intensity

    Major

    The discussion says there was no demyelination in regions with disrupted connectivity, but the figure caption reports reduced myelin intensity in V2, a region identified as having disrupted connectivity.

  • A nonsignificant genotype effect is called significant

    Minor

    The reported p-value of 0.951 contradicts the statement that betweenness centrality has a significant main effect of genotype.

2 of 2

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Authors
Al-Amin, M. M., Grandjean, J., Klohs, J., & Kim, J.
Affiliations
  • Indiana University School of Medicine
  • Radboud University Medical Center (NL)
  • University of Zurich (CH)
Corresponding author
Kim, Jungsu
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2020-04-28
DOI
10.1101/2020.04.27.064634
OpenAlex
W3021782801
Semantic Scholar
34ccb7c77067705a85d7600db2426d6175f4d953
Cited by
2
References
94
Citations by year
2024: 1 · 2021: 1
Type
posted content
Language
en
Open access
Licence
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • National Institutes of Health (R01AG053500, R01AG053242, R21AG050804)
  • National Institute on Aging (R01AG054102)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
amyloid-beta, Alzheimer's disease, white matter microstructure, structural connectivity, entorhinal cortex, fiber density, perineuronal nets, neurofilament light chain, axonal integrity, network efficiency, fixel-based analysis, myelination

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