Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

Article type: Research Article

Authors: Serra, Laura^{a; *} | D’Amelio, Marcello^{b; c} | Esposito, Sharon^a | Di Domenico, Carlotta^a | Koch, Giacomo^{d; e} | Marra, Camillo^f | Mercuri, Nicola Biagio^{g; h} | Caltagirone, Carloⁱ | Artusi, Carlo Alberto^j | Lopiano, Leonardo^j | Cercignani, Mara^{a; k} | Bozzali, Marco^{j; l}

Affiliations: [a] Neuroimaging Laboratory, Fondazione Santa Lucia, IRCCS, Rome, Italy | [b] Laboratory Molecular Neurosciences, Fondazione Santa Lucia, IRCCS, Rome, Italy | [c] Unit of Molecular Neurosciences, Department of Medicine, University Campus-Biomedico, Rome, Italy | [d] Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Fondazione Santa Lucia, IRCCS, Rome, Italy | [e] Section of Human Physiology, University of Ferrara, Ferrara, Italy | [f] Institute of Neurology, Catholic University, Rome, Italy | [g] Laboratory of Experimental Neurology, Fondazione Santa Lucia, IRCCS, Rome, Italy | [h] Department of Systems Medicine, University of Rome ‘Tor Vergata’, Rome, Italy | [i] Department of Clinical and Behavioural Neurology, Fondazione Santa Lucia, IRCCS, Rome, Italy | [j] ‘Rita Levi Montalcini’ Department of Neuroscience University of Torino, Turin, Italy | [k] Cardiff University Brain Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales, United Kingdom | [l] Department of Neuroscience, Brighton & Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom

Correspondence: [*] Correspondence to: Laura Serra, PhD, Via Ardeatina 306, 00179 Rome, Italy. Tel.: +39 06 5150 1493; Fax: +39 06 5150 1213; E-mail: [email protected].

Abstract: Background:Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective:In this study, we longitudinally investigated by resting-state fMRI (rs-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods:A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and rs-fMRI to assess VTA connectivity at baseline and at follow-up. Results:At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-Converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion:This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression.

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, dopaminergic system, functional connectivity, restingstate MRI, ventral tegmental area

DOI: 10.3233/JAD-210171

Journal: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 985-1000, 2021