Spontaneous and perturbation-based EEG cortical excitability markers are associated with plasma p-tau181 concentration in healthy middle-aged adults

Ruben Perellón-Alfonso^{1

2

3}, Kilian Abellaneda-Pérez^{3

4

5}, Indre Pileckyte⁶, María Cabello-Toscano^{1

2}, Lídia Mulet-Pons^{1

2}, Lídia Vaqué-Alcázar^{1

2

7}, Gabriele Cattaneo^{3

4

5}, María Redondo-Camós^{3

4

5}, Goretti España-Irla^{8

9

10}, Selma Delgado-Gallen^{3

4

5}, Javier Solana Sánchez^{3

4

5}, Henrik Zetterberg^{11

12

13

14

15

16}, Jose M Tormos¹⁷, Nicolai Franzmeier^{18

19

20}, Alvaro Pascual-Leone^{21

22

23}, David Bartrés-Faz^{1

2

3}

Affiliations

¹ Department of Medicine, Faculty of Medicine and Health Sciences, and Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
² Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
³ Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴ Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
⁵ Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain.
⁶ Center for Brain and Cognition, Pompeu Fabra University, Barcelona, Spain.
⁷ Sant Pau Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Department of Psychology, Northeastern University, Boston, MA, USA.
⁹ Center for Cognitive & Brain Health, Northeastern University, Boston, MA, USA.
¹⁰ Department of Physical Therapy, Movement, & Rehabilitation Sciences, Northeastern University, Boston, MA, USA.
¹¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹³ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁴ UK Dementia Research Institute at UCL, London, UK.
¹⁵ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁶ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁷ Centro de Investigación Translacional San Alberto Magno - Facultad Ciencias de la Salud - Universidad Católica de Valencia, Spain.
¹⁸ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU, Munich, Germany.
¹⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
²⁰ University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sweden.
²¹ Hinda and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA.
²² Department of Neurology, Harvard Medical School, Boston, MA, USA.
²³ Linus Health, Inc., Boston, MA, USA.

PMID: 39759333
PMCID: PMC11700258
DOI: 10.1016/j.heliyon.2024.e41118

Spontaneous and perturbation-based EEG cortical excitability markers are associated with plasma p-tau181 concentration in healthy middle-aged adults

Ruben Perellón-Alfonso et al. Heliyon. 2024.

. 2024 Dec 10;10(24):e41118.

doi: 10.1016/j.heliyon.2024.e41118. eCollection 2024 Dec 30.

Authors

Affiliations

¹ Department of Medicine, Faculty of Medicine and Health Sciences, and Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
² Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
³ Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴ Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
⁵ Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain.
⁶ Center for Brain and Cognition, Pompeu Fabra University, Barcelona, Spain.
⁷ Sant Pau Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Department of Psychology, Northeastern University, Boston, MA, USA.
⁹ Center for Cognitive & Brain Health, Northeastern University, Boston, MA, USA.
¹⁰ Department of Physical Therapy, Movement, & Rehabilitation Sciences, Northeastern University, Boston, MA, USA.
¹¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹³ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁴ UK Dementia Research Institute at UCL, London, UK.
¹⁵ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁶ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁷ Centro de Investigación Translacional San Alberto Magno - Facultad Ciencias de la Salud - Universidad Católica de Valencia, Spain.
¹⁸ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU, Munich, Germany.
¹⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
²⁰ University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sweden.
²¹ Hinda and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA.
²² Department of Neurology, Harvard Medical School, Boston, MA, USA.
²³ Linus Health, Inc., Boston, MA, USA.

PMID: 39759333
PMCID: PMC11700258
DOI: 10.1016/j.heliyon.2024.e41118

Abstract

In early-stage Alzheimer's disease (AD) amyloid-β (Aβ) deposition can induce neuronal hyperactivity, thereby potentially triggering activity-dependent neuronal secretion of phosphorylated tau (p-tau), ensuing tau aggregation and spread. Therefore, cortical excitability is a candidate biomarker for early AD detection. Moreover, lowering neuronal excitability could potentially complement strategies to reduce Aβ and tau buildup. There is, however, a lack of understanding of the relationship between cortical excitability and p-tau increase in vivo. Therefore, in a sample of 658 healthy middle-aged (between the ages of 40 and 65) participants of the Barcelona Brain Health Initiative cohort study, we examined the relation of blood-based tau, phosphorylated at amino acid 181 (p-tau181), reflecting neuronal p-tau secretion; neurofilament light chain (NfL), as a passively released control for p-tau181; and electroencephalography (EEG) markers of cortical excitability. A subsample of 47 participants also completed a controlled brain perturbation approach via transcranial magnetic stimulation (TMS) with concurrent EEG. Results show that both spontaneous (i.e., resting-state) and perturbation-based TMS-EEG markers, are associated with blood p-tau181, particularly in older individuals. The perturbation-based marker was a significantly more sensitive predictor of p-tau181 concentration than the spontaneous resting state EEG-based marker. The relationships observed are not present for the NfL control. These results show that relationships between p-tau181 and cortical excitability are present in healthy middle-aged subjects and that p-tau181 increases may reflect activity-dependent secretion.

Keywords: Alzheimer's disease; EEG; Tau; Transcranial magnetic stimulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alvaro Pascual-Leone reports a relationship with Neuroelectrics that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Magstim Inc. that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with TetraNeuron that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Skin2Neuron that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with MedRhythms that includes: consulting or advisory. Alvaro Pascual-Leone reports a relationship with Hearts-Radiant that includes: consulting or advisory. Henrik Zetterberg reports a relationship with AbbVie that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Acumen that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alector that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alzinova that includes: consulting or advisory. Henrik Zetterberg reports a relationship with ALZPath that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Annexon that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Apellis that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Artery Therapeutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with AZTherapies that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Cognito Therapeutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with CogRx that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Denali that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Eisai that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Merry Life that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Nervgen that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Novo Nordisk that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Optoceutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Passage Bio, Inc. that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Pinteon Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Prothena that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Red Abbey Labs that includes: consulting or advisory. Henrik Zetterberg reports a relationship with reMYND that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Roche that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Samumed that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Siemens Healthineers that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Triplet Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Wave that includes: consulting or advisory. David Bartres-Faz reports a relationship with Linus Health that includes: consulting or advisory. A.P-L is co-founder of TI solutions and co-founder and chief medical officer of Linus Health where he has shares and share-options. A.P-L is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and applications of noninvasive brain stimulation in various neurological disorders; as well as digital biomarkers of cognition and digital assessments for early diagnosis of dementia. H.Z. has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
Johnson-Neyman interval plot illustrating the age interval at which the relationship between perturbation-based excitability and p-tau181 is significant (i.e., 61–65 years of age). n.s. = non-significant.

**Fig. 2**
Johnson-Neyman interval plot illustrating the age interval at which the relationship between spontaneous excitability and p-tau181 is significant (i.e., 54–65 years of age). n.s. = non-significant.

**Fig. 3**
Illustration of EEG cortical excitability markers. A) illustrates the TMS-evoked perturbation of the EEG and the spatial region of interest in source space (grey transparent patch over L-PFC) and, B) the time-window taken from the TMS-evoked EEG timeseries to compute the perturbation-based marker of VGSC excitability (grey transparency spanning from 160 to 240 ms after TMS pulse). C) illustrates the recording of resting state EEG and, D) the decomposition of the power spectrum at rest to isolate the aperiodic component, the slope of which we take here as the spontaneous marker for excitation/inhibition balance. In both B and D panels, grand average waveforms for all participants included in the study are shown. EEG, electroencephalography; L-PFC, left prefrontal cortex; VGSC, voltage-gated sodium channel.

See this image and copyright information in PMC

References

1. Targa Dias Anastacio H., Matosin N., Ooi L. Neuronal hyperexcitability in Alzheimer's disease: what are the drivers behind this aberrant phenotype? Transl. Psychiatry. 2022;12(1) doi: 10.1038/s41398-022-02024-7. - DOI - PMC - PubMed
1. Zadey S., Buss S.S., McDonald K., Press D.Z., Pascual-Leone A., Fried P.J. Higher motor cortical excitability linked to greater cognitive dysfunction in Alzheimer's disease: results from two independent cohorts. Neurobiol. Aging. 2021;108:24–33. doi: 10.1016/j.neurobiolaging.2021.06.007. - DOI - PMC - PubMed
1. Busche M.A., Chen X., Henning H.A., Reichwald J., Staufenbiel M., Sakmann B., Konnerth A. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(22):8740–8745. doi: 10.1073/pnas.1206171109. - DOI - PMC - PubMed
1. Schultz M.K., Gentzel R., Usenovic M., Gretzula C., Ware C., Parmentier-Batteur S., Schachter J.B., Zariwala H.A. Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice. Neurobiol. Dis. 2018;118(July):161–176. doi: 10.1016/j.nbd.2018.07.003. - DOI - PubMed
1. Zhang Y., Chen H., Li R., Sterling K., Song W. Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future. Signal Transduct. Targeted Ther. 2023;8(1):1–26. doi: 10.1038/s41392-023-01484-7. - DOI - PMC - PubMed

LinkOut - more resources

Full Text Sources
- Elsevier Science
- PubMed Central

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Spontaneous and perturbation-based EEG cortical excitability markers are associated with plasma p-tau181 concentration in healthy middle-aged adults

Affiliations

Spontaneous and perturbation-based EEG cortical excitability markers are associated with plasma p-tau181 concentration in healthy middle-aged adults

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources