Epicentral Disruption of Structural Connectivity in Alzheimer's Disease
Open accessAbstract
Summary: Aims: Neurodegenerative changes observed in Alzheimer's disease (AD) have been suggested to begin at the entorhinal cortex and hippocampus and then to propagate in a stereotypical fashion. Using diffusion‐weighted imaging, we test whether disruption of structural connectivity in AD is centered on these “epicenters of disease”. Methods: Fifteen healthy controls, 14 amnestic mild cognitive impairment (aMCI), 13 mild, and 15 moderate patients with AD were enrolled. The percentages of affected connections directly linking to the epicenter (named first ring) and to nodes with topological distance 2 from the epicenter (named second ring) were calculated. Results: For the group of aMCI patients, just 5.3% of the first ring (n.s.) and 2.9% of the second ring (n.s.) connections were affected. However, for mild AD there was disruption involving 20% of the first ring (P < 0.0001) and 10.3% of the second ring (P < 0.0001) connections. In the moderate AD group, a stronger effect was observed, with 38.0% of the first ring (P < 0.0001) connections and 17.9% of the second ring (P < 0.0001) connections affected. Conclusion: Our results favor an epicentral disruption of structural connectivity in aMCI and AD around entorhinal and hippocampal regions, consistent with the transneuronal spread hypothesis.
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Studies suggest that AD pathogenesis targets high-traffic hub regions in the brain, spreading from epicenters to secondary networks as the disease progresses.
“Additionally, studies suggest that AD pathogenesis targets high-traffic hub regions in the brain, spreading from epicenters to secondary networks as the disease progresses (Buckner et al., 2009; Dai et al., 2015; Mallio et al., 2015; Stam et al., 2009; Zhou, Gennatas, Kramer, Miller, & Seeley, 2012; Zhou & Seeley, 2014).”
From Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer’s disease (2018) · cites this paper as Mallio et al., 2015
The Summary (p. 1) and Conclusion (pp. 6–7) support disruption spreading outward from entorhinal and hippocampal epicenters as AD severity increases. But the Conclusion (p. 8) reports that testing high-traffic hub regions as alternative epicenters did not reproduce this pattern; the authors say total connectional flow did not explain their results. Thus this paper does not support the high-traffic-hub part of the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDisrupted 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).”
From Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis (2020) · cites this paper as Mallio et al., 2015
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Cites
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Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease
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Impaired default network functional connectivity in autosomal dominant Alzheimer disease
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Badea, A., Kane, L., Anderson, R. J., Qi, Y., Foster, M., Cofer, G. P., Medvitz, N., Buckley, A. F., Badea, A. K., Wetsel, W. C., et al. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.08.014 · Cited by 39 · see citing works
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“…targets high-traffic hub regions in the brain, spreading from epicenters to secondary Network Neuroscience 242 networks as the disease progresses (Buckner et al., 2009; Dai et al., 2015; Mallio et al., 2015; Stam et al., 2009; Zhou, Gennatas, Kramer, Miller, & Seeley, 2012; Zhou & Seeley, 2014).”
BackgroundDisrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis
Al-Amin, M. M., Grandjean, J., Klohs, J., & Kim, J. (2020) · doi:10.1101/2020.04.27.064634 · Cited by 2 · see citing works
“Disrupted structural connectivity in the EC is also a feature of AD (Mallio et al., 2015).”
Background
- Authors
- Mallio, C. A., Schmidt, R., de Reus, M. A., Vernieri, F., Quintiliani, L., Curcio, G., Beomonte Zobel, B., Quattrocchi, C. C., & van den Heuvel, M. P.
- Affiliations
- Università Campus Bio-Medico (IT)
- University Medical Center Utrecht (NL)
- Brain Center Rudolf Magnus Department of Psychiatry, University Medical Center Utrecht Utrecht the Netherlands
- University of L'Aquila (IT)
- Departmental Faculty of Medicine and Surgery Unit of Diagnostic Imaging Università Campus Bio‐Medico di Roma Rome Italy
- Corresponding author
- Mallio, Carlo Augusto
- ORCID
- Venue
- CNS Neuroscience & Therapeutics
- Publisher
- Wiley
- Published
- 2015-04-21
- Volume
- 21
- Issue
- 10
- Pages
- 837-845
- ISSN
- 1755-5930 (ISSN-L)
- 1755-5949
- PMC
- PMC6493130
- OpenAlex
- W2108307693
- Cited by
- 39
- References
- 7
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 1 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 2
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- CNS Neuroscience & Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, public-domain)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Iris (University of Trento) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- VENI (#451-12-001)
- Netherlands Organization for Scientific Research (NWO)
- Fellowship of the Brain Center Rudolf Magnus
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Keywords
- Alzheimer's disease, structural connectivity, entorhinal cortex, hippocampus, amnestic mild cognitive impairment, diffusion-weighted imaging, network topology, disease propagation
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mental Status Schedule, Neural Pathways, Severity of Illness Index, Anisotropy, Cognitive Dysfunction
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