Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Article type: Research Article

Authors: Fried, Peter J.^{a; *} | Schilberg, Lukas^{a; b} | Brem, Anna-Katharine^{a; c} | Saxena, Sadhvi^{a; d} | Wong, Bonnie^{a; g} | Cypess, Aaron M.^{e; f} | Horton, Edward S.^f | Pascual-Leone, Alvaro^{a; *}

Affiliations: [a] Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Interventional Cognitive Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA | [b] Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands | [c] Department of Experimental Psychology, University of Oxford, Oxford, UK | [d] Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical School, Baltimore, MD, USA | [e] Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA | [f] Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA | [g] Frontotemporal Dementia Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

Correspondence: [*] Correspondence to: Dr. Peter J. Fried and Dr. Alvaro Pascual-Leone, Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, 330 Brookline Ave, KS 158, Boston, MA, 02215, USA. Tel.: +1 617 667 0203; Fax: +1 617 975 5322; E-mail: pfried@bidmc.harvard.edu (P.J. Fried); apleone@bidmc.harvard.edu (A. Pascual-Leone).

Abstract: Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

Keywords: Cognitive aging, neuroplasticity, transcranial magnetic stimulation, type 2 diabetes mellitus, verbal learning

DOI: 10.3233/JAD-160505

Journal: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 89-100, 2017