Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer’s Disease

Cope, Zackary A.; Murai, Takeshi; Rizzo, Stacey J. Sukoff

doi:10.3389/fnagi.2022.805063

Cited by 5 publications

(6 citation statements)

References 194 publications

(277 reference statements)

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“…The LEC is the first cortical region to undergo end-stage cellular neurodegeneration 5 in AD, specifically, Layer II 2 excitatory cells 7 . Conversely, one of the earliest pathophysiological alterations seen in both humans with AD, and in mouse models of early- and late-onset AD pathology 3,4,11 is altered local circuit excitability 6,61,62 . In agreement with our ex vivo mechanistic cellular findings here, hyperactivity has been shown to preferentially emerge in the LEC region in vivo 6 .…”

Section: Discussionmentioning

confidence: 99%

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Goettemoeller,

Banks,

Kumar

et al. 2023

Preprint

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Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability1. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer’s Disease2-4. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type-specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer’s. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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Section: Discussionmentioning

confidence: 99%

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Goettemoeller,

Banks,

Kumar

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The LEC is the first cortical region to undergo end-stage cellular neurodegeneration 5 in AD, specifically, Layer II 2 excitatory cells 7 . Conversely, one of the earliest pathophysiological alterations seen in both humans with AD, and in mouse models of early-and late-onset AD pathology 3,4,11 is altered local circuit excitability 6,61,62 . In agreement with our ex vivo mechanistic cellular findings here, hyperactivity has been shown to preferentially emerge in the LEC region in vivo 6 .…”

Section: Discussionmentioning

confidence: 99%

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Rowan,

Goettemoeller,

Banks

et al. 2023

Preprint

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Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability1. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer’s Disease2-4. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer’s. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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“…The PLI first becomes significant from timestep 6, the JPE from timestep 3 and the PLT from timestep 6. D) Results for the beta band (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The AECc and the PLI show a declining trend but no significant results except for the AECc at timestep 8.…”

Section: Sensitivity Of Fc Biomarkers To Changes In the Add Modelmentioning

confidence: 99%

“…The yield may be increased with long term EEG monitoring, or the use of MEG instead of EEG, but these approaches are demanding for patients, expensive and not always generally available [11,[13][14][15]. Several alternative measures of NH which can be computed from EEG or MEG recordings have been proposed [16][17][18]. Functional connectivity (FC) are very promising candidates as biomarkers of NH since connections between distance brain regions consist mostly axons of excitatory neurons.…”

Section: Introductionmentioning

confidence: 99%

Network Hyperexcitability in Early-Stage Alzheimer’s Disease: Evaluation of Functional Connectivity Biomarkers in a Computational Disease Model

Stam,

de Haan

2024

JAD

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Background: There is increasing evidence from animal and clinical studies that network hyperexcitability (NH) may be an important pathophysiological process and potential target for treatment in early Alzheimer’s disease (AD). Measures of functional connectivity (FC) have been proposed as promising biomarkers for NH, but it is unknown which measure has the highest sensitivity for early-stage changes in the excitation/inhibition balance. Objective: We aim to test the performance of different FC measures in detecting NH at the earliest stage using a computational approach. Methods: We use a whole brain computational model of activity dependent degeneration to simulate progressive AD pathology and NH. We investigate if and at what stage four measures of FC (amplitude envelope correlation corrected [AECc], phase lag index [PLI], joint permutation entropy [JPE] and a new measure: phase lag time [PLT]) can detect early-stage AD pathophysiology. Results: The activity dependent degeneration model replicates spectral changes in line with clinical data and demonstrates increasing NH. Compared to relative theta power as a gold standard the AECc and PLI are shown to be less sensitive in detecting early-stage NH and AD-related neurophysiological abnormalities, while the JPE and the PLT show more sensitivity with excellent test characteristics. Conclusions: Novel FC measures, which are better in detecting rapid fluctuations in neural activity and connectivity, may be superior to well-known measures such as the AECc and PLI in detecting early phase neurophysiological abnormalities and in particular NH in AD. These markers could improve early diagnosis and treatment target identification.

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Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer’s Disease

Cited by 5 publications

References 194 publications

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Network Hyperexcitability in Early-Stage Alzheimer’s Disease: Evaluation of Functional Connectivity Biomarkers in a Computational Disease Model

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