Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer’s Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design

Article type: Research Article

Authors: Pievani, Michela^{a; *} | Mega, Anna^a | Quattrini, Giulia^{a; b} | Guidali, Giacomo^c | Ferrari, Clarissa^d | Cattaneo, Annamaria^{e; f} | D’Aprile, Ilari^e | Mascaro, Lorella^g | Gasparotti, Roberto^h | Corbo, Daniele^h | Brignani, Debora^{c; i} | Bortoletto, Marta^c

Affiliations: [a] Laboratory of Alzheimer’s Neuroimaging and Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [b] Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy | [c] Neurophysiology Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [d] Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [e] Biological Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [f] Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy | [g] Medical Physics Unit, ASST Spedali Civili Di Brescia, Brescia, Italy | [h] Neuroradiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy | [i] Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Correspondence: [*] Correspondence to: Michela Pievani, PhD, Lab Alzheimer’s Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, via Pilastroni 4, 25125 Brescia, Italy. Tel.: +39 030 3501261; E-mail: [email protected].

Abstract: Background:Default mode network (DMN) dysfunction is well established in Alzheimer’s disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. Objective:This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ɛ4 allele. Methods:We will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. Results:We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. Conclusion: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.

Keywords: Alzheimer’s disease, at-risk healthy subjects, APOE ɛ4 allele, default mode network, functional connectivity, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210659

Journal: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1877-1889, 2021