Association Between Insulin Resistance, Plasma Leptin, and Neurocognition in Vascular Cognitive Impairment

Article type: Research Article

Authors: Smith, Patrick J.^{a; *} | Mabe, Stephanie^a | Sherwood, Andrew^a | Babyak, Michael A.^a | Doraiswamy, P. Murali^a | Welsh-Bohmer, Kathleen A.^a | Kraus, William^b | Burke, James^c | Hinderliter, Alan^d | Blumenthal, James A.^a

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA | [b] Department of Medicine, Duke University Medical Center, Durham, NC, USA | [c] Department of Neurology, Duke University Medical Center, Durham, NC, USA | [d] Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

Correspondence: [*] Correspondence to: Patrick J. Smith, PhD, MPH, Departments of Psychiatry and Medicine; Duke University Medical Center, Durham, NC 27710, USA. Tel.: +1 919 684 3828; Fax: +1 919 684 8629; E-mail: patrick.j.smith@dm.duke.edu.

Abstract: Background:Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. Objective:To examine metabolic mechanisms underlying the association between obesity and neurocognition. Methods:We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. Results:Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p = 0.043), CRP (p < 0.001), and leptin (p < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (β= –0.16, p = 0.024) and Verbal Memory (β= –0.16, p = 0.030), but not Visual Memory (β= 0.05, p = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (β= –0.12, p = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function. Conclusions:In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance.

Keywords: Cognitive function, executive function, inflammation, insulin sensitivity, leptin, metabolic function, obesity

DOI: 10.3233/JAD-190569

Journal: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 921-929, 2019