Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease

Lisa Vermunt^{1

2}, Courtney L Sutphen³, Ellen Dicks^{1

4}, Diederick M de Leeuw¹, Ricardo F Allegri⁵, Sarah B Berman⁶, David M Cash⁷, Jasmeer P Chhatwal⁸, Carlos Cruchaga³, Gregory S Day⁹, Michael Ewers^{10

11}, Martin R Farlow¹², Nick C Fox^{13

14}, Bernardino Ghetti¹⁵, Neill R Graff-Radford⁹, Jason Hassenstab³, Mathias Jucker^{11

15}, Celeste M Karch³, Jens Kuhle¹⁶, Christoph Laske^{11

15}, Johannes Levin^{11

17}, Colin L Masters^{18

19}, Eric McDade³, Hiroshi Mori²⁰, John C Morris³, Richard J Perrin³, Oliver Preische^{11

15}, Peter R Schofield²¹, Marc Suárez-Calvet^{22

23

24}, Chengjie Xiong³, Philip Scheltens^{1

25}, Charlotte E Teunissen², Pieter Jelle Visser²⁶, Randall J Bateman³, Tammie L S Benzinger³, Anne M Fagan³, Brian A Gordon³, Betty M Tijms¹

Affiliations

¹ Alzheimer center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Programme Neurodegeneration, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands.
² Neurochemistry Laboratory, Departmentt of Laboratory Medicine, Amsterdam Neuroscience, Programme Neurodegeneration, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands.
³ Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁵ Instituto de Investigaciones Neurológicas FLENI, Buenos Aires, Argentina.
⁶ Department of Neurology, Alzheimer's Disease Research Center, and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁷ Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3AR, UK.
⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Mayo Clinic Florida, Jacksonville, FL 32224, USA.
¹⁰ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University Munich, 81377 Munich, Germany.
¹¹ German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany.
¹² Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
¹³ Dementia Research Institute at UCL, University College London Institute of Neurology, London W1T 7NF, UK.
¹⁴ Department of Neurodegenerative Disease, Dementia Research Centre, London WC1N 3AR, UK.
¹⁵ Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany.
¹⁶ Neurologic Clinic and Policlinic, University Hospital and University Basel, 4031 Basel, Switzerland.
¹⁷ Ludwig-Maximilians-Universität München, D-80539 München, Germany.
¹⁸ Florey Institute, Melbourne, Parkville Vic 3052, Australia.
¹⁹ The University of Melbourne, Melbourne, Parkville Vic 3052, Australia.
²⁰ Department of Clinical Neuroscience, Osaka City University Medical School, 558-8585 Osaka, Japan.
²¹ Neuroscience Research Australia & School of Medical Sciences, NSW 2052 Sydney, Sydney, Australia.
²² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain.
²³ IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.
²⁴ Servei de Neurologia, Hospital del Mar, 08003 Barcelona, Spain.
²⁵ Life Science Partners, 1071 DV Amsterdam, The Netherlands.
²⁶ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, 6229 ER Maastricht, Netherlands.

PMID: 39440304
PMCID: PMC11495221
DOI: 10.1093/braincomms/fcae357

Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease

Lisa Vermunt et al. Brain Commun. 2024.

. 2024 Oct 9;6(5):fcae357.

doi: 10.1093/braincomms/fcae357. eCollection 2024.

Authors

Affiliations

¹ Alzheimer center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Programme Neurodegeneration, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands.
² Neurochemistry Laboratory, Departmentt of Laboratory Medicine, Amsterdam Neuroscience, Programme Neurodegeneration, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands.
³ Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁵ Instituto de Investigaciones Neurológicas FLENI, Buenos Aires, Argentina.
⁶ Department of Neurology, Alzheimer's Disease Research Center, and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁷ Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3AR, UK.
⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Mayo Clinic Florida, Jacksonville, FL 32224, USA.
¹⁰ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University Munich, 81377 Munich, Germany.
¹¹ German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany.
¹² Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
¹³ Dementia Research Institute at UCL, University College London Institute of Neurology, London W1T 7NF, UK.
¹⁴ Department of Neurodegenerative Disease, Dementia Research Centre, London WC1N 3AR, UK.
¹⁵ Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany.
¹⁶ Neurologic Clinic and Policlinic, University Hospital and University Basel, 4031 Basel, Switzerland.
¹⁷ Ludwig-Maximilians-Universität München, D-80539 München, Germany.
¹⁸ Florey Institute, Melbourne, Parkville Vic 3052, Australia.
¹⁹ The University of Melbourne, Melbourne, Parkville Vic 3052, Australia.
²⁰ Department of Clinical Neuroscience, Osaka City University Medical School, 558-8585 Osaka, Japan.
²¹ Neuroscience Research Australia & School of Medical Sciences, NSW 2052 Sydney, Sydney, Australia.
²² Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain.
²³ IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.
²⁴ Servei de Neurologia, Hospital del Mar, 08003 Barcelona, Spain.
²⁵ Life Science Partners, 1071 DV Amsterdam, The Netherlands.
²⁶ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, 6229 ER Maastricht, Netherlands.

PMID: 39440304
PMCID: PMC11495221
DOI: 10.1093/braincomms/fcae357

Abstract

The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer's disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer's disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

Keywords: autosomal dominant Alzheimer disease; axonal damage; inflammation; neuronal injury; structural covariance network.

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Conflict of interest statement

C.C.: receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, interpretation of data; or in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of ADx Healthcare and Vivid Genomics Marty Farlow: Grant/Research Support from AbbVie, ADCS Posiphen, AstraZeneca, Biogen, Eisai, Eli Lilly, Genentech, Novartis, Suven Life Sciences, Ltd., vTv Therapeutics; Consultant/Advisory Boards/DSMB Boards for Allergan, Avanir, AZTherapies, Biogen MA Inc., Cerecin (formerly Accera), Chemigen, Cognition Therapeutics, Cortexyme, Danone, Eisai Inc., Eli Lilly, Longeveron, Green Valley, Medavante, Otsuka Pharmaceutical, Proclara, Neurotrope Bioscience, Samumed, Takeda, vTv Therapeutics, Zhejian Hisun Pharmaceuticals; patent Elan Johannes Levin reports speaker’s fees from Bayer Vital, speaker’s fees from Willi Gross Foundation, consulting fees from Axon Neuroscience, consulting fees from Ionis Pharmaceuticals, non-financial support from Abbvie, MODAG compensation for part time CMO, Thieme medical publishers and W. Kohlhammer GmbH medical publishers author fees, outside the submitted work. E.M.: NIA (research Funding); Eli Lilly-DSMB; ESAI—CMS; Alzamend—scientific advisory board. P.S. is partner at LSP Invester fund and has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham and EIP Pharma. Outside of this manuscript, R.J.B. reports grant/research/clinical trial support: NIH, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, Cure Alzheimer's Fund, the Tau SILK Consortium (AbbVie, Biogen and Eli Lilly), Janssen, and an anonymous foundation. R.J.B. reports consulting fees/honoraria from Janssen, Pfizer, Roche, Eisai, and Merck. R.J.B. reports equity ownership interest/advisory board income from C2N Diagnostics. All other authors report no disclosures.

Figures

**Figure 1**
**Associations between CSF biomarkers and grey matter networks for mutation carriers and non-carriers.** Linear models predicting the small-world coefficient with the respective CSF biomarkers, adjusted for sex. All biomarkers were significantly associated to the small-world coefficient (P < 0.05). We tested the interaction with mutation status. All of the interactions, except for the AB42/40 ratio and sTREM2, were significant (P < 0.05), meaning that the strength of the relationship between the CSF biomarker and the grey matter network value dependent on mutation status. See for the test details in Table 2. The graphs show the predicted values with 95% confidence intervals. Each panel (**A–I**) represents a biomarker. Aβ, Amyloid beta; pTau, phosphorylated Tau; tTau, total Tau; SNAP-25, Synaptosomal-Associated Protein 25 kDa; Ng, Neurogranin; NfL, Neurofilament Light; VILIP-1, visinin-like protein 1; YKL40, Chitinase 3-like 1; sTREM2, soluble TREM2 relative to a reference sample.

**Figure 2**
**Associations between CSF biomarkers and grey matter networks within mutation carriers by disease stage.** Linear model predicting the small-world coefficient with the respective CSF biomarkers, adjusted for sex. We tested the interaction with disease severity within the mutation carriers. None of the interactions with mutation type are significant (<0.05). The graphs show the predicted values with 95% confidence intervals. See Supplementary Table 2 for test statistics. Each panel (**A–I**) represents a biomarker. Aβ, Amyloid beta; pTau, phosphorylated Tau; tTau, total Tau; SNAP-25, Synaptosomal-Associated Protein 25 kDa; Ng, Neurogranin; NfL, Neurofilament Light; VILIP-1, visinin-like protein 1; YKL40, Chitinase 3-like 1; sTREM2, soluble TREM2 relative to a reference sample.

See this image and copyright information in PMC

References

1. He Y, Chen Z, Evans A. Structural insights into aberrant topological patterns of large-scale cortical networks in Alzheimer's disease. J Neurosci. 2008;28(18):4756–4766. - PMC - PubMed
1. Tijms BM, Series P, Willshaw DJ, Lawrie SM. Similarity-based extraction of individual networks from gray matter MRI scans. Cereb Cortex. 2012;22(7):1530–1541. - PubMed
1. Alexander-Bloch A, Giedd JN, Bullmore E. Imaging structural co-variance between human brain regions. Nat Rev Neurosci. 2013;14(5):322–336. - PMC - PubMed
1. Tijms BM, Wink AM, de Haan W, et al. . Alzheimer's disease: Connecting findings from graph theoretical studies of brain networks. Neurobiol Aging. 2013;34(8):2023–2036. - PubMed
1. Dai Z, He Y. Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer's disease. Neurosci Bull. 2014;30(2):217–232. - PMC - PubMed

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Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease

Affiliations

Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials