Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series¹

Article type: Research Article

Authors: Dhaynaut, Maeva^{a; 2} | Sprugnoli, Giulia^{b; 2} | Cappon, Davide^b | Macone, Joanna^b | Sanchez, Justin S.^{a; c} | Normandin, Marc D.^a | Guehl, Nicolas J.^a | Koch, Giacomo^{d; e} | Paciorek, Rachel^b | Connor, Ann^b | Press, Daniel^b | Johnson, Keith^{a; c} | Pascual-Leone, Alvaro^{f; g} | El Fakhri, Georges^{a; 2; *} | Santarnecchi, Emiliano^{a; b; 2; *}

Affiliations: [a] Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [b] Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA | [c] Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [d] Santa Lucia Foundation IRCCS, Rome, Italy | [e] Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy | [f] Hinda and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA | [g] Department of Neurology, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Emiliano Santarnecchi, PhD, Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Tel.: +1 617 667 0326; E-mail: [email protected] and Georges El Fakhri, PhD, DABR, Director, Gordon Center for Medical Imaging, Co-Director, Division of Nuclear Medicine & Molecular Imaging, Massachusetts General Hospital, Nathaniel & Diana Alpert Professor of Radiology, Harvard Medical School, Boston, MA, USA. Tel.: +1 617 953 5085; E-mail: [email protected].

Note: [1] Minor corrections to the author names and affiliations were made on [1 March 2022].

Note: [2] These authors contributed equally to this work.

Abstract: Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild to moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

Keywords: Amyloid, dementia, electroencephalography, gamma, neurostimulation, positron-emission tomography, protein clearance, protein misfolding, tau, transcranial electrical stimulation

DOI: 10.3233/JAD-215072

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1667-1676, 2022