Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer's disease continuum

  1. Kok Pin Ng
  2. Xing Qian
  3. Kwun Kei Ng
  4. Fang Ji
  5. Pedro Rosa-Neto
  6. Serge Gauthier
  7. Nagaendran Kandiah
  8. Juan Helen Zhou  Is a corresponding author
  9. for the Alzheimer's Disease Neuroimaging Initiative
  1. National Neuroscience Institute, Singapore
  2. National University of Singapore, Singapore
  3. McGill University, Canada

Abstract

Background: Large-scale neuronal network breakdown underlies memory impairment in Alzheimer's disease (AD). However, the differential trajectories of the relationships between network organization and memory across pathology and cognitive stages in AD remain elusive. We determined whether and how the influences of individual-level structural and metabolic covariance network integrity on memory varied with amyloid pathology across clinical stages without assuming a constant relationship.

Methods: 708 participants from the Alzheimer's Disease Neuroimaging Initiative were studied. Individual-level structural and metabolic covariance scores in higher-level cognitive and hippocampal networks were derived from magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography using seed-based partial least square analyses. The non-linear associations between network scores and memory across cognitive stages in each pathology group were examined using sparse varying coefficient modelling.

Results: We showed that the associations of memory with structural and metabolic networks in the hippocampal and default mode regions exhibited pathology-dependent differential trajectories across cognitive stages using sparse varying coefficient modelling. In amyloid pathology group, there was an early influence of hippocampal structural network deterioration on memory impairment in the preclinical stage, and a biphasic influence of the angular gyrus-seeded default mode metabolic network on memory in both preclinical and dementia stages. In non- amyloid pathology groups, in contrast, the trajectory of the hippocampus-memory association was opposite and weaker overall, while no metabolism covariance networks were related to memory. Key findings were replicated in a larger cohort of 1280 participants.

Conclusions: Our findings highlight potential windows of early intervention targeting network breakdown at the preclinical AD stage.

Funding: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). We also acknowledge the funding support from the Duke-NUS/Khoo Bridge Funding Award (KBrFA/2019-0020) and NMRC Open Fund Large Collaborative Grant (OFLCG09May0035).

Data availability

ADNI data used in this manuscript are publicly available at adni.loni.usc.edu, subject to adherence to the ADNI Data Use Agreement and publications' policies (https://ida.loni.usc.edu/collaboration/access/appLicense.jsp). Guidelines to apply for data access can be found in https://adni.loni.usc.edu/data-samples/access-data/#access_data. Codes used in this manuscript are available at https://github.com/hzlab/2021Qian_ADNI_FDG . The repository is currently private, but will be made public after manuscript acceptance for publication.

The following previously published data sets were used

Article and author information

Author details

  1. Kok Pin Ng

    Department of Neurology, National Neuroscience Institute, Singapore, Singapore
    Competing interests
    No competing interests declared.
  2. Xing Qian

    Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  3. Kwun Kei Ng

    Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0584-7679
  4. Fang Ji

    Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  5. Pedro Rosa-Neto

    Translational Neuroimaging Laboratory, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9116-1376
  6. Serge Gauthier

    Department of Psychiatry, McGill University, Montreal, Canada
    Competing interests
    Serge Gauthier, received consulting fees from CERVEAU Therapeutics, Biogen Canada, Roche Canada, TauRx, honoraria from Biogen Canada, and payment for participation on the DIAN-TU Washington University drug selection committee..
  7. Nagaendran Kandiah

    Department of Neurology, National Neuroscience Institute, Singapore, Singapore
    Competing interests
    Nagaendran Kandiah, received grants from Novartis Pharmaceuticals and Schwabe Pharmaceuticals, honoraria and support (for travel and/or meetings) from Eisai Pharmaceuticals, Novartis, Schwabe and Lundbeck, and participated on the Asian Society Against Dementia committee and Vascog Asia..
  8. Juan Helen Zhou

    Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    For correspondence
    helen.zhou@nus.edu.sg
    Competing interests
    Juan Helen Zhou, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0180-8648

Funding

Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904)

  • Kok Pin Ng
  • Xing Qian
  • Kwun Kei Ng
  • Fang Ji
  • Pedro Rosa-Neto
  • Serge Gauthier
  • Nagaendran Kandiah
  • Juan Helen Zhou

Duke-NUS Medical School (Duke-NUS/Khoo Bridge Funding Award (KBrFA/2019-0020))

  • Juan Helen Zhou

National Medical Research Council (NMRC Open Fund Large Collaborative Grant (OFLCG09May0035))

  • Juan Helen Zhou

DoD Alzheimer's Disease Neuroimaging Initiative (Department of Defense award number W81XWH-12-2-0012)

  • Kok Pin Ng
  • Xing Qian
  • Kwun Kei Ng
  • Fang Ji
  • Pedro Rosa-Neto
  • Serge Gauthier
  • Nagaendran Kandiah
  • Juan Helen Zhou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease (AD).The ADNI study was approved by the Institutional Review Boards of all of the participating institutions and informed written consent was obtained from all participants at eachsite.

Reviewing Editor

  1. Jeannie Chin, Baylor College of Medicine, United States

Publication history

  1. Received: February 9, 2022
  2. Preprint posted: March 2, 2022 (view preprint)
  3. Accepted: September 2, 2022
  4. Accepted Manuscript published: September 2, 2022 (version 1)
  5. Version of Record published: September 15, 2022 (version 2)
  6. Version of Record updated: September 20, 2022 (version 3)

Copyright

© 2022, Ng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 556
    Page views
  • 178
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kok Pin Ng
  2. Xing Qian
  3. Kwun Kei Ng
  4. Fang Ji
  5. Pedro Rosa-Neto
  6. Serge Gauthier
  7. Nagaendran Kandiah
  8. Juan Helen Zhou
  9. for the Alzheimer's Disease Neuroimaging Initiative
(2022)
Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer's disease continuum
eLife 11:e77745.
https://doi.org/10.7554/eLife.77745

Further reading

    1. Cancer Biology
    2. Medicine
    Huan-Huan Chen, Tie-Ning Zhang ... Tao Zhang
    Research Article Updated

    Background:

    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

    Methods:

    We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).

    Results:

    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

    Conclusions:

    Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.

    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).

    1. Medicine
    Zhongjie Fu, Anders K Nilsson ... Lois EH Smith
    Review Article

    At preterm birth, the retina is incompletely vascularized. Retinopathy of prematurity (ROP) is initiated by the postnatal suppression of physiological retinal vascular development that would normally occur in utero. As the neural retina slowly matures, increasing metabolic demand including in the peripheral avascular retina, leads to signals for compensatory but pathological neovascularization. Currently, only late neovascular ROP is treated. ROP could be prevented by promoting normal vascular growth. Early perinatal metabolic dysregulation is a strong but understudied risk factor for ROP and other long-term sequelae of preterm birth. We will discuss the metabolic and oxygen needs of retina, current treatments, and potential interventions to promote normal vessel growth including control of postnatal hyperglycemia, dyslipidemia and hyperoxia-induced retinal metabolic alterations. Early supplementation of missing nutrients and growth factors and control of supplemental oxygen promotes physiological retinal development. We will discuss the current knowledge gap in retinal metabolism after preterm birth.