Effects of Alzheimer’s and Vascular Pathologies on Structural Connectivity in Early- and Late-Onset Alzheimer’s Disease

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

Alzheimer's disease is marked by amyloid plaques and neurofibrillary tangles present in gray matter.

“Alzheimer’s disease (AD) is the most common type of neurodegenerative disease, marked by amyloid plaques and neurofibrillary tangles present in gray matter (Blennow et al., 2006; Bastin and Salmon, 2014).”

• cites Blennow et al., 2006 sourceNot checked — no full text of the source
• cites Bastin and Salmon, 2014 sourceCould not verify

  The retrieved passages are chiefly bibliography entries under “Field Citation Ratio > 2.21 Relative Citation Ratio” (page unavailable), not statements about Alzheimer’s pathology. Searches for amyloid plaques, neurofibrillary tangles, and gray matter found no passage in our copy that establishes the attributed claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

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

DTI metrics or structural connectome alterations showed correlations with amyloid burden or levels of cerebrospinal fluid amyloid and tau.

“Diffusion tensor imaging (DTI) metrics or structural connectome alterations showed correlations with amyloid burden (Racine et al., 2014) or levels of cerebrospinal fluid amyloid and tau (Tucholka et al., 2018).”

• cites Racine et al., 2014 sourceSupported
• cites Tucholka et al., 2018 sourcePartly supported

  The Results (‘Correlations of connections with biomarkers’; page not available) report correlations between structural connectivity and CSF Aβ42 in both samples. They also report a significant correlation with p-tau in one sample, but it was not reproduced in the other; the Discussion says tau-related associations were less consistent. Thus the citation supports the amyloid finding but overstates the tau finding if read as a general correlation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Permutation-based NBS and CBS were proposed to cope with the problem of multiple comparison while preventing too conservative correction in connectivity analysis using group differences or correlation coefficients, respectively.

“Permutation-based network-based statistics (NBS) (Zalesky et al., 2010) and cluster-based statistics (CBS) (Han et al., 2013) were performed for each process, which were proposed to cope with the problem of multiple comparison while preventing too conservative correction in connectivity analysis using group differences or correlation coefficients, respectively.”

• cites Zalesky et al., 2010 sourceNot checked — no full text of the source
• cites Han et al., 2013 sourceSupported

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

The spatial atrophy pattern of neurodegenerative diseases resembles a distinct intrinsic functional connectivity.

“the spatial atrophy pattern of neurodegenerative diseases resembles a distinct intrinsic functional connectivity (Buckner et al., 2005; Seeley et al., 2009)”

• cites Buckner et al., 2005 sourcePartly supported

  The MRI maps of longitudinal structural atrophy and Figure 6 show that atrophy in Alzheimer’s disease overlaps posterior regions associated with the default-activity network. The paper does not establish that atrophy patterns across neurodegenerative diseases resemble distinct intrinsic functional-connectivity networks; it examines Alzheimer’s disease and compares atrophy chiefly with default activity, amyloid deposition, and metabolism. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Seeley et al., 2009 sourceSupported

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

Vascular pathology is part of the multifactorial mechanisms present in LOAD.

“Vascular pathology is also known to be part of the multifactorial mechanisms present in LOAD (Ortner et al., 2015; Iturria-Medina et al., 2016).”

• cites Ortner et al., 2015 sourceNot checked — no full text of the source
• cites Iturria-Medina et al., 2016 sourceSupported

Classified as probably not a substantial claim.

Higher vascular burden represented by white matter hyperintensities is associated with a reduced functional connectome in AD.

“Higher vascular burden represented by white matter hyperintensities (WMHs) also have been shown to be associated with a reduced functional connectome in AD (Taylor et al., 2017).”

• cites Taylor et al., 2017 sourceSupported

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

In a previous THK study with early AD patients, the precuneus was the most prominent AD-specific THK retention area, and the spatial pattern of THK uptake showed significant similarity with functional connectivity.

“In a previous THK study with early AD patients, the precuneus was the most prominent AD-specific THK retention area, and the spatial pattern of THK uptake showed significant similarity with functional connectivity (Yokoi et al., 2018).”

• cites Yokoi et al., 2018 sourceSupported

The quote only partly states this claim.

In LOAD, disrupted connectivity correlated with white matter hyperintensities.

“late-onset AD patients had disrupted connectivity correlated with amyloid deposition, white matter hyperintensities, and lacunes”

May combine two claims.

EOAD patients exhibited significantly disrupted white matter connectivity compared to young controls, with 68 edges showing significantly lower weights (p = 0.0162).

“Both patient groups exhibited significantly disrupted connectivity compared to their control counterparts with distinct patterns.”

• Also stated in: § Distinct Patterns of WM Connectivity Disruption in AD · plain

  “A total of 68 edges had significantly lower weights in EOAD compared to YC (p = 0.0162).”

May combine two claims.

LOAD patients exhibited significantly disrupted white matter connectivity compared to old controls, with 59 edges showing significantly disrupted connectivity (p = 0.0176).

“Both patient groups exhibited significantly disrupted connectivity compared to their control counterparts with distinct patterns.”

• Also stated in: § Distinct Patterns of WM Connectivity Disruption in AD · plain

  “Meanwhile, when comparing LOAD and OC, 59 edges were found to be significantly disrupted (p = 0.0176)”

May combine two claims.

In EOAD, all edges in the identified subnetwork related to global THK retention were connected to the parietal lobule, which were connected to occipital regions the most (42.9%).

“With the representative regions involved in the parietal lobule, all edges in the identified subnetwork related to global THK retention were connected to the parietal lobule, which were connected to occipital regions the most (42.9%).”

May combine two claims.

MMSE and CDR SOB did not differ significantly between EOAD and LOAD.

“Years of education and disease duration did not differ significantly in EOAD and LOAD nor did MMSE or CDR SOB.”

May combine two claims.

LOAD showed fewer items with a significant relationship, and the correlation coefficients were also lower than in EOAD.

“On the contrary, LOAD showed fewer items with a significant relationship, and the correlation coefficients were also lower than in EOAD”

May combine two claims.

MMSE (r = 0.4693, FDR-corrected p = 0.0233) or CDR SOB (r = −0.4618, FDR-corrected p = 0.0233) were associated with the edge weights having close relationships with global FLUTE retention.

“MMSE (r = 0.4693, FDR-corrected p = 0.0233) or CDR SOB (r = −0.4618, FDR-corrected p = 0.0233) were associated with the edge weights having close relationships with global FLUTE retention.”

May combine two claims.

The edges were located over all brain regions in EOAD patients, but connections linked with the parietal lobe comprised the largest proportion.

“The edges were located over all brain regions in EOAD patients, but connections linked with the parietal lobe comprised the largest proportion.”

May combine two claims.

In EOAD regional THK retention, local values resulted in two clusters, and the size of the largest cluster was nine (p = 0.0004).

“Local values resulted in two clusters, and the size of the largest cluster was nine (p = 0.0004).”

May combine two claims.

Scores in attention, language, visuospatial, and executive function domains had significantly positive correlations with connectivity disruption.

“Scores in the domain of attention (digit span forward and backward), language (K-BNT), visuospatial (RCFT, copy), and executive function (COWAT, animal, supermarket and phonemic; Stroop test; TMT-A and B) had significantly positive correlations.”

May combine two claims.

In EOAD global THK retention, the number of clusters was two, and the largest size was four (p = 0.0070).

“In the global view, the number of clusters was two, and the largest size was four (p = 0.0070).”

May combine two claims.

The number of APOE ε4 carriers and proportion of amyloid-positive patients was not different between the EOAD and LOAD groups.

“The number of APOE ε4 carriers and proportion of amyloid-positive patients was not different between the EOAD and LOAD groups.”

May combine two claims.

Years of education and disease duration did not differ significantly between EOAD and LOAD.

“Years of education and disease duration did not differ significantly in EOAD and LOAD nor did MMSE or CDR SOB.”

The quote only partly states this claim.

Global cognition scores like MMSE and CDR SOB were significantly associated with connectivity disruption.

“Global cognition scores like MMSE and CDR SOB were also significantly associated with connectivity disruption.”

May combine two claims.

Either lacune numbers or WMH volume had the same representative region of the left middle occipital gyrus, as well as the left calcarine additionally in WMH volume analysis.

“Either lacune numbers or WMH volume had the same representative region of the left middle occipital gyrus, as well as the left calcarine additionally in WMH volume analysis”

May combine two claims.

In EOAD, edges in the resultant subnetwork were most connected to the parietal lobule, but some edges were connected within occipital and temporal regions.

“Edges in resultant subnetwork were most connected to the parietal lobule, but some edges were connected within occipital and temporal regions.”

May combine two claims.

In EOAD, both global and regional THK retentions showed an increasing trend with greater connectivity disruptions.

“Both global and regional THK retentions showed an increasing trend with greater connectivity disruptions.”

May combine two claims.

In LOAD, representative regions were additionally identified in the temporal and limbic lobes, and connection disruptions between the frontal and limbic lobes were remarkable compared to EOAD.

“In LOAD, representative regions were additionally identified in the temporal and limbic lobes, and connection disruptions between the frontal and limbic lobes were remarkable compared to EOAD.”

May combine two claims.

The left superior parietal gyrus and angular gyrus were identified as the representative regions associated with regional THK retention in our study, as well as the right middle occipital and temporal gyrus.

“The left superior parietal gyrus and angular gyrus were identified as the representative regions associated with regional THK retention in our study, as well as the right middle occipital and temporal gyrus.”

May combine two claims.

With THK retention, all and half of the representative regions were derived in the parietal lobule, and connections to the parietal or occipital lobules were found in common.

“With THK retention, all and half of the representative regions were derived in the parietal lobule, and connections to the parietal or occipital lobules were found in common”

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

Recent tau PET studies with [18F]flortaucipir showed that EOAD had greater tau burden in the neocortex compared to LOAD patients.

“Recent tau PET studies with [18F]flortaucipir showed that EOAD had greater tau burden in the neocortex compared to LOAD patients (Cho et al., 2017; Schöll et al., 2017).”

• cites Cho et al., 2017 sourceNot checked — no full text of the source
• cites Schöll et al., 2017 sourceNot checked — no full text of the source

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

[18F]-THK5351 PET showed greater retention in the association cortex including prefrontal, parietal, precuneus, and posterior cingulate cortex in EOAD patients compared to LOAD.

“[18F]-THK5351 PET also showed greater retention in the association cortex including prefrontal, parietal, precuneus, and posterior cingulate cortex in EOAD patients compared to LOAD (Noh et al., 2017).”

• cites Noh et al., 2017 sourceNot checked — no full text of the source

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

In amyloid PET studies, EOAD patients have exhibited higher amyloid burden in the parietal cortex, basal ganglia, and thalamus.

“In amyloid PET studies, EOAD patients have exhibited higher amyloid burden in the parietal cortex (Ossenkoppele et al., 2012), basal ganglia, and thalamus (Cho et al., 2013b).”

• cites Ossenkoppele et al., 2012 sourceNot checked — no full text of the source
• cites Cho et al., 2013bNot matched

  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).

One experienced neurologist blinded to other patient data reviewed the number and location of lacunes.

“One experienced neurologist who was blinded to other patient data reviewed the number and location of lacunes using the FLAIR and T1 and T2 images.”

Classified as probably not a substantial claim.

Different patterns of damage in interhemispheric structural and functional connectivity of EOAD and LOAD may lead to distinct clinical profiles.

“A recent study has shown that there exist different patterns of damage in terms of the interhemispheric structural and functional connectivity of EOAD and LOAD, and these patterns may lead to distinct clinical profiles (Li et al., 2018).”

• cites Li et al., 2018Not matched

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

May combine two claims.

Previous studies addressed only single pathological factor or could not demonstrate associations with brain-wide regional burden of these factors using in vivo PET imaging.

“However, these previous studies addressed only single pathological factor or could not demonstrate associations with brain-wide regional burden of these factors using in vivo positron emission tomography (PET) imaging.”

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

Multiple comparisons for cognitive scores were corrected using the Benjamini-Hochberg false discovery rate method.

“Multiple comparisons for scores were corrected using the Benjamini–Hochberg false discovery rate (FDR) method (Benjamini and Hochberg, 1995).”

• cites Benjamini and Hochberg, 1995 sourceNot checked — no full text of the source

May combine two claims.

FA-weighted structural networks were used because FA values represent the level of microstructural organization of WM tracts and are associated with the efficacy of connections.

“We used FA-weighted structural networks for the statistical analysis since FA values have been considered to represent the level of microstructural organization of WM tracts (Beaulieu, 2002), known to be associated with the efficacy of the connections (Ewing-Cobbs et al., 2006; Gold et al., 2007)”

• cites Beaulieu, 2002 sourceNot checked — no full text of the source
• cites Ewing-Cobbs et al., 2006Not checked — no full text of the source
• cites Gold et al., 2007 sourceNot checked — no full text of the source

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

The precuneus is functionally variable and plays an important role in the default mode network (DMN), which is known to be disrupted in EOAD and LOAD.

“The precuneus is functionally variable and plays an important role in the default mode network (DMN), which is known to be disrupted in EOAD and LOAD (Utevsky et al., 2014; Badhwar et al., 2017).”

• cites Utevsky et al., 2014; Badhwar et al., 2017Not matched

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

May combine two claims.

In previous studies, EOAD patients have exhibited higher amyloid and tau burden in the parietal cortex and widespread cortical atrophy especially in the parietal cortex.

“In previous studies, EOAD patients have exhibited higher amyloid and tau burden in the parietal cortex (Ossenkoppele et al., 2012; Cho et al., 2017) and have shown widespread cortical atrophy especially in the parietal cortex (Noh et al., 2014a).”

• cites Ossenkoppele et al., 2012; Cho et al., 2017Not matched

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

• cites Noh et al., 2014aNot matched

  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).

Some previous studies have shown more pronounced DMN hypoconnectivity in EOAD compared to LOAD.

“Some previous studies have shown more pronounced DMN hypoconnectivity in EOAD compared to LOAD (Adriaanse et al., 2014; Thomas et al., 2014).”

• cites Adriaanse et al., 2014; Thomas et al., 2014Not matched

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

May combine two claims.

Individual pathology-related WM network disruptions did not seem to be associated necessarily with cognitive declines in LOAD compared to EOAD exhibiting significant correlations with various specific neuropsychological test scores.

“Individual pathology-related WM network disruptions did not seem to be associated necessarily with cognitive declines in LOAD compared to EOAD exhibiting significant correlations with various specific neuropsychological test scores.”

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

We did not include subcortical structures of medial temporal regions including the hippocampus or amygdala in our analyses, which could influence the results especially in LOAD patients.

“We did not include subcortical structures of medial temporal regions including the hippocampus or amygdala in our analyses, which could influence the results especially in LOAD patients.”

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

In CAA patients, connectivity disruption was more pronounced in the occipital lobe and related with higher amyloid load and vascular markers including WMH volume.

“In CAA patients, connectivity disruption was more pronounced in the occipital lobe and related with higher amyloid load and vascular markers including WMH volume (Reijmer et al., 2014).”

• cites Reijmer et al., 2014 sourceNot checked — no full text of the source

May combine two claims.

It is possible that SVD may result in preferential BBB disruption in the posterior circulation, which could induce increased amyloid deposition in these areas, including the occipital region.

“Therefore, it is possible that SVD may result in preferential BBB disruption in the posterior circulation, which could induce increased amyloid deposition in these areas, including the occipital region (Noh et al., 2014b).”

• cites Noh et al., 2014bNot matched

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

May combine two claims.

Tau-related connectivity disruption in EOAD may be at least partly explained by amyloid beta triggering toxic tau and tau causing synaptic dysfunction and neuronal death.

“Therefore, tau-related connectivity disruption in EOAD may be at least partly explained by this.”

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

Greater tau burden exists in the parieto-occipital area with EOAD patients compared to LOAD.

“consistently with previous researches reporting that greater tau burden exists in the parieto-occipital area with EOAD patients compared to LOAD (Cho et al., 2017).”

• cites Cho et al., 2017 sourceNot checked — no full text of the source

May combine two claims.

Tau burden is a key influential factor and may mediate the distinct clinical patterns of EOAD.

“This sheds light on tau burden as a key influential factor and may imply that it mediates the distinct clinical patterns of EOAD.”

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

The current study investigated the association of various pathologies with heterogeneity between EOAD and LOAD using cross-sectional data, which could limit the interpretation of the results.

“Finally, the current study investigated the association of various pathologies with heterogeneity between EOAD and LOAD using cross-sectional data, which could limit the interpretation of the results.”

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

In a previous study, WMH were associated with amyloid burden especially in the occipital areas.

“In a previous study, WMH were associated with amyloid burden especially in the occipital areas (Grimmer et al., 2012; Noh et al., 2014b).”

• cites Grimmer et al., 2012; Noh et al., 2014bNot matched

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

May combine two claims.

WM network disruption in both AD groups appeared to be distinct, with disruption in EOAD patients apparently affected by tau and related astrogliosis, which strongly correlated with most of the cognitive functions except for memory.

“WM network disruption in both AD groups appeared to be distinct, with disruption in EOAD patients apparently affected by tau and related astrogliosis, which strongly correlated with most of the cognitive functions except for memory as being compatible with the general features of EOAD.”

May combine two claims.

LOAD patients showed associations with WM disruption with amyloid or vascular pathology; however, this disruption could not explain the cognitive profile of LOAD.

“LOAD patients showed associations with WM disruption with amyloid or vascular pathology; however, this disruption could not explain the cognitive profile of LOAD.”

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

The number of gradient directions we used was low to form enough degrees of freedom for high-order models such as HARDI and DSI.

“High-order models such as high angular resolution diffusion tensor (HARDI) (Tuch et al., 2002) and diffusion spectrum imaging (DSI) (Wedeen et al., 2005) can further resolve the crossing fiber issues, but the number of gradient directions we used was low to form enough degrees of freedom for those approaches.”

May combine two claims.

Studies have reported that amyloid beta triggers the formation of toxic tau, and the toxic form of tau causes synaptic dysfunction and neuronal death.

“Studies have reported that amyloid beta triggers the formation of toxic tau, and the toxic form of tau causes synaptic dysfunction and neuronal death (Hurtado et al., 2010; Bloom, 2014).”

• cites Hurtado et al., 2010; Bloom, 2014Not matched

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

May combine two claims.

Our findings show that EOAD and LOAD have distinct topographies and pathogenesis of WM connectivity disruption.

“Our findings show that EOAD and LOAD have distinct topographies and pathogenesis of WM connectivity disruption.”

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

Because FA could be affected non-linearly by amyloid load, analyses regarding connectivity require caution.

“In addition, because it was shown that FA could be affected non-linearly by amyloid load in a previous study (Wolf et al., 2015), analyses regarding connectivity require caution.”

• cites Wolf et al., 2015 sourceNot checked — no full text of the source

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

Many recent studies about AD, mostly indicating LOAD, reported that there are synergistic or mediated effects between pathological factors on AD progression.

“Many recent studies about AD, mostly indicating LOAD, also reported that there are synergistic or mediated effects between pathological factors (e.g., tau and amyloid, or amyloid and vascular dysregulation) on AD progression (Iturria-Medina et al., 2016; Pascoal et al., 2017; Hanseeuw et al., 2019).”

• cites Iturria-Medina et al., 2016; Pascoal et al., 2017; Hanseeuw et al., 2019Not matched

  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). May combine two claims.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Gachon University Gil Medical Center, and participants provided written informed consent.

“The studies involving human participants were reviewed and approved by the Institutional Review Board of Gachon University Gil Medical Center. The patients/participants provided their written informed consent to participate in this study.”