Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer’s disease

Kamalini G Ranasinghe; Parul Verma; Chang Cai; Xihe Xie; Kiwamu Kudo; Xiao Gao; Hannah Lerner; Danielle Mizuiri; Amelia Strom; Leonardo Iaccarino; Renaud La Joie; Bruce L Miller; Maria Luisa Gorno-Tempini; Katherine P Rankin; William J Jagust; Keith Vossel; Gil D Rabinovici; Ashish Raj; Srikantan S Nagarajan

doi:10.7554/eLife.77850

eLife (May 2022)

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer’s disease

Kamalini G Ranasinghe,
Parul Verma,
Chang Cai,
Xihe Xie,
Kiwamu Kudo,
Xiao Gao,
Hannah Lerner,
Danielle Mizuiri,
Amelia Strom,
Leonardo Iaccarino,
Renaud La Joie,
Bruce L Miller,
Maria Luisa Gorno-Tempini,
Katherine P Rankin,
William J Jagust,
Keith Vossel,
Gil D Rabinovici,
Ashish Raj,
Srikantan S Nagarajan

Affiliations

Kamalini G Ranasinghe: ORCiD; Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Parul Verma: ORCiD; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Chang Cai: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Xihe Xie: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Kiwamu Kudo: ORCiD; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States; Medical Imaging Business Center, Ricoh Company, Kanazawa, Japan
Xiao Gao: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Hannah Lerner: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Danielle Mizuiri: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Amelia Strom: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Leonardo Iaccarino: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Renaud La Joie: ORCiD; Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Bruce L Miller: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Maria Luisa Gorno-Tempini: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
Katherine P Rankin: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States
William J Jagust: ORCiD; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
Keith Vossel: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States; Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Gil D Rabinovici: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Ashish Raj: ORCiD; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
Srikantan S Nagarajan: ORCiD; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States

DOI: https://doi.org/10.7554/eLife.77850
Journal volume & issue: Vol. 11

Abstract

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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 and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography, 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 and 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 (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer’s Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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