Functional MRI Signal Fluctuations: A Preclinical Biomarker for Cognitive Impairment in Type 2 Diabetes?

  1. Robert S. Sherwin1
  1. 1Section of Endocrinology, Yale University School of Medicine, New Haven, CT
  2. 2Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT
  1. Corresponding author: Robert S. Sherwin, robert.sherwin{at}

Type 2 diabetes mellitus (T2DM) is associated with macrovascular and microvascular complications as well as an increased risk for cognitive impairment (CI), ranging from mild memory impairment to fully developed dementia (1). Both vascular dementia (VD) and Alzheimer disease (AD) dementia are increased in patients with T2DM. However, it is not clear if T2DM directly causes CI and dementia or if the two disorders share a common pathophysiological process (2).

Insulin resistance, hyperglycemia, and hypoglycemia have all been implicated as risk factors for CI in T2DM (3). However, their relative importance remains uncertain. The possibility that altered brain insulin action plays a role is consistent with human data showing that AD is associated with decreased insulin receptor expression in the brain (4), impaired insulin signaling (5), and decreased insulin levels in the cerebrospinal fluid (CSF) (6). Furthermore, insulin delivery directly into the hippocampus enhances spatial memory in nondiabetic rats, whereas this response to intrahippocampal insulin is impaired in diet-induced obese rats (7). In small clinical trials, intranasal insulin delivery appears to improve memory function in patients with CI and AD (8).

Functional MRI, based on the blood oxygenation level–dependent (BOLD) contrast mechanism, has become an important tool to investigate the brain’s neurophysiologic response to specific stimuli or cognitive tasks. In contrast, resting-state functional MRI (rs-fMRI) measures spontaneous low-frequency oscillations in the BOLD …

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