Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease
- University of California, San Francisco, United States
- University of California, Berkeley, United States
- University of California, Los Angeles, United States
Abstract
Background: Neuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.
Methods: Using empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography (PET), in patients with AD.
Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.
Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.
Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimer's Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.
Data availability
Data and materials availability: All data associated with this study are present in the paper or in the Supplementary Materials. Anonymized subject data will be shared on request from qualified investigators for the purposes of replicating procedures and results, and for other non-commercial research purposes within the limits of participants' consent. Correspondence and material requests should be addressed to Kamalini.ranasinghe@ucsf.edu
Article and author information
Author details
Kamalini Ranasinghe
Funding
National Institute on Aging (K08AG058749)
- Kamalini Ranasinghe
National Institute on Aging (K23 AG038357)
- Keith Vossel
National Institutes of Health
- Bruce L Miller
- William J Jagust
- Gil Rabinovici
- Ashish Raj
- Srikantan Nagarajan
Alzheimer's Association
- Kamalini Ranasinghe
- Keith Vossel
Larry L. Hillblom Foundation
- Kamalini Ranasinghe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Informed consent was obtained from all participants and the study was approved by the Institutional Review Board (IRB) at UCSF (UCSF-IRB 10-02245).
Reviewing Editor
- Inna Slutsky, Tel Aviv University, Israel
Publication history
- Received: February 12, 2022
- Preprint posted: March 10, 2022 (view preprint)
- Accepted: May 19, 2022
- Accepted Manuscript published: May 26, 2022 (version 1)
- Version of Record published: June 22, 2022 (version 2)
Copyright
© 2022, Ranasinghe 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.
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Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease
eLife 11:e77850.
https://doi.org/10.7554/eLife.77850
Further reading
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- Medicine
- Physics of Living Systems
Background:
Postoperative knee instability is one of the major reasons accounting for unsatisfactory outcomes, as well as a major failure mechanism leading to total knee arthroplasty (TKA) revision. Nevertheless, subjective knee instability is not well defined clinically, plausibly because the relationships between instability and implant kinematics during functional activities of daily living remain unclear. Although muscles play a critical role in supporting the dynamic stability of the knee joint, the influence of joint instability on muscle synergy patterns is poorly understood. Therefore, this study aimed to understand the impact of self-reported joint instability on tibiofemoral kinematics and muscle synergy patterns after TKA during functional gait activities of daily living.
Methods:
Tibiofemoral kinematics and muscle synergy patterns were examined during level walking, downhill walking, and stair descent in eight self-reported unstable knees after TKA (3M:5F, 68.9 ± 8.3 years, body mass index [BMI] 26.1 ± 3.2 kg/m2, 31.9 ± 20.4 months postoperatively), and compared against 10 stable TKA knees (7M:3F, 62.6 ± 6.8 years, 33.9 ± 8.5 months postoperatively, BMI 29.4 ± 4.8 kg/m2). For each knee joint, clinical assessments of postoperative outcome were performed, while joint kinematics were evaluated using moving video-fluoroscopy, and muscle synergy patterns were recorded using electromyography.
Results:
Our results reveal that average condylar A-P translations, rotations, as well as their ranges of motion were comparable between stable and unstable groups. However, the unstable group exhibited more heterogeneous muscle synergy patterns and prolonged activation of knee flexors compared to the stable group. In addition, subjects who reported instability events during measurement showed distinct, subject-specific tibiofemoral kinematic patterns in the early/mid-swing phase of gait.
Conclusions:
Our findings suggest that accurate movement analysis is sensitive for detecting acute instability events, but might be less robust in identifying general joint instability. Conversely, muscle synergy patterns seem to be able to identify muscular adaptation associated with underlying chronic knee instability.
Funding:
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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- Medicine
Supervision is one important way to socialize Ph.D. candidates into open and responsible research. We hypothesized that one should be more likely to identify open science practices (here publishing open access and sharing data) in empirical publications that were part of a Ph.D. thesis when the Ph.D. candidates’ supervisors engaged in these practices compared to those whose supervisors did not or less often did. Departing from thesis repositories at four Dutch University Medical centers, we included 211 pairs of supervisors and Ph.D. candidates, resulting in a sample of 2062 publications. We determined open access status using UnpaywallR and Open Data using Oddpub, where we also manually screened publications with potential open data statements. Eighty-three percent of our sample was published openly, and 9% had open data statements. Having a supervisor who published open access more often than the national average was associated with an odds of 1.99 to publish open access. However, this effect became nonsignificant when correcting for institutions. Having a supervisor who shared data was associated with 2.22 (CI:1.19–4.12) times the odds to share data compared to having a supervisor that did not. This odds ratio increased to 4.6 (CI:1.86–11.35) after removing false positives. The prevalence of open data in our sample was comparable to international studies; open access rates were higher. Whilst Ph.D. candidates spearhead initiatives to promote open science, this study adds value by investigating the role of supervisors in promoting open science.
