Brain Imaging and Behavior

, Volume 13, Issue 1, pp 53–64 | Cite as

Identify a shared neural circuit linking multiple neuropsychiatric symptoms with Alzheimer’s pathology

  • Xixi Wang
  • Ping Ren
  • Mark Mapstone
  • Yeates Conwell
  • Anton P. Porsteinsson
  • John J. Foxe
  • Rajeev D. S. Raizada
  • Feng LinEmail author
  • and the Alzheimer’s Disease Neuroimaging Initiative
Original Research


Neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28 AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions’ functional connectivity classified symptomatic subjects across individual NPS at 69.46–81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration.


Alzheimer’s disease Functional magnetic resonance imaging Mild cognitive impairment Multivariate pattern analysis Neuropsychiatric symptoms 



We thank Andrew J. Anderson, Benjamin D. Zinszer, Carol A. Jew, and Jiayi Zhou for helpful discussions and comments.

Compliance with ethical standards


The manuscript writing was funded by the Alzheimer’s Association New Investigator Grant (NIRG-14-317353) and National Institutes of Health R01 grant (R01NR015452 and R21AG053193) to F. Lin.

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). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Conflict of interest

X. Wang, P. Ren, M. Mapstone, Y. Conwell, A.P. Porsteinsson, J.J. Foxe, R.D.S. Raizada, and F. Lin declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Xixi Wang
    • 1
  • Ping Ren
    • 2
  • Mark Mapstone
    • 3
  • Yeates Conwell
    • 4
  • Anton P. Porsteinsson
    • 4
  • John J. Foxe
    • 5
  • Rajeev D. S. Raizada
    • 6
  • Feng Lin
    • 2
    • 4
    • 5
    • 6
    Email author
  • and the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Department of Biomedical EngineeringUniversity of RochesterRochesterUSA
  2. 2.School of NursingUniversity of Rochester Medical CenterRochesterUSA
  3. 3.Department of NeurologyUniversity of California-IrvineIrvineUSA
  4. 4.Department of PsychiatryUniversity of Rochester Medical CenterRochesterUSA
  5. 5.Department of NeuroscienceUniversity of Rochester Medical CenterRochesterUSA
  6. 6.Department of Brain and Cognitive SciencesUniversity of RochesterRochesterUSA

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