Effect of intranasally administered insulin on cerebral blood flow and perfusion; a randomized experiment in young and older adults

Abstract

Insulin, a vasoactive modulator regulating peripheral and cerebral blood flow, has been consistently linked to aging and longevity. In this proof of principle study, using a randomized, double-blinded, placebo-controlled crossover design, we explored the effects of intranasally administered insulin (40IU) on cerebral blood flow (CBF) and perfusion in older (60-69 years, n=11) and younger (20-26 years, n=8) adults. Changes in CBF through the major cerebropetal arteries were assessed via phase contrast MR-angiography, and regional cortical tissue perfusion via pseudo-continuous arterial spin labelling. Total flow through the major cerebropetal arteries was unchanged in both young and old. In the older participants, intranasal insulin compared to placebo increased perfusion through the occipital gray matter (65.2±11.0 mL/100g/min vs 61.2±10.1 mL/100g/min, P=0.001), and in the thalamus (68.28±6.75 mL/100g/min versus 63.31±6.84 mL/100g/min, P=0.003). Thus, intranasal insulin improved tissue perfusion of the occipital cortical brain region and the thalamus in older adults.

Keywords: aging; cerebral blood flow; continuous arterial spin labelling (CASL); intranasal insulin; magnetic resonance imaging (MRI); phase contrast MR angiography.

Figure 1. Glucose and insulin trajectories during the experimental period

Concentrations (every 10 minutes) of glucose and insulin in blood serum over a 90- minute period, comprising measurements before and after intranasal application of insulin (40IU insulin Actrapid, blue line) or placebo (saline, red dotted line) using ViaNase nasal atomizer. Blue arrow indicates timing of intranasal administration of insulin or placebo. Data is presented as mean with standard error in (A) glucose trajectory in young and (B) insulin trajectory in young (C) glucose trajectory in older and (D) insulin trajectory in older adults.

Figure 2. Gray matter perfusion maps after intranasal administration of placebo and insulin

Left panel (A and B) represents the gray matter perfusion map after intranasal placebo administration and the right panel (C and D) the perfusion map after intranasal insulin administration for one representative older participant. The top row shows an increase in the gray matter perfusion of occipital lobe (illustrated by blue oval) after intranasal administration of insulin compared to placebo. The bottom row shows an increase in gray matter perfusion in the parietal lobe (illustrated by blue rectangle) after intranasal administration of insulin compared to placebo. Only the gray matter was included for calculation of perfusion after intranasal administration of insulin compared to placebo.

Figure 3. Paired individual gray matter perfusion measurements for placebo and insulin conditions

Left panel represents the gray matter perfusion in the parietal lobe as paired data for placebo and intranasal insulin per individual subject in the young and the older group. The right panel represents the gray matter perfusion in the occipital lobe.

Figure 4. Flowchart of experimental procedures related to cerebral blood flow and perfusion measurements

After an overnight fast and baseline measures, the study day started at 08.00 with blood sample withdrawal for baseline measures, after which subjects received either the intranasal insulin or intranasal placebo treatment. MRI scanning began 20 mins later, including survey/structural MRI scans, flow and perfusion scans.

Figure 5. MR images of the vasculature measured with phase contrast MR angiography imaging for Quantitative Flow (QF)

Typical placement of the QF phase-contrast slice (C) through the right internal carotid artery (RCAR), left internal carotid artery (LCAR) and the basilar artery (BAS) using the sagittal (A) and coronal (B) localizer angiograms. ROI's were drawn around the three arteries in slice C to measure flow.