4958

Intranasal Insulin Enhances Resting Neurovascular Fluctuations in Type 2 Diabetes
Zongpai Zhang1, Faizan Khan2, Peter Novak2, Christos Mantzoros3, Long Ngo3, Vera Novak2, and Weiying Dai1
1State University of New York at Binghamton, Binghamton, NY, United States, 2Department of Neurology, Harvard Medical School, Boston, ME, United States, 3Department of Medicine, Harvard Medical School, Boston, ME, United States

Synopsis

We aimed to investigate the effect of intranasal insulin (INI) on cognition, balance, and brain neurovascular activity in type 2 diabetes mellitus (T2DM) participants of the MemAID trial. Cognition, balance, and brain neurovascular fluctuations - amplitude of low-frequency fluctuations (ALFF) were measured in 11 subjects before and after 24-week treatment with INI or placebo. INI treatment significantly increased ALFF in the medial-frontal region. The ALFF increases at the end-of INI treatment were associated with improved balance. These findings suggest that INI may increase brain neurovascular activity in T2DM in the regions related to balance control and sustained attention.

Introduction

T2DM alters cognition1-4 and balance5. Resting-state functional MR imaging (rsfMRI) is a powerful tool for evaluating spontaneous brain activity6. The ALFF map from rsfMRI quantifies the intensity of neurovascular fluctuation at a single voxel level7. ALFF are diminished in T2DM as compared to healthy subjects8-10. We have demonstrated that a single INI dose acutely improves visuospatial memory11 and resting-state connectivity12. We investigated the long-term effects of INI on ALFF and the relationship of INI-induced ALFF changes with changes of cognition and balance in the MemAID trial13.

Methods

Eleven T2DM participants (eight INI, three placebo) completed the baseline and end-of-treatment scans after 24 weeks using a GE Discovery MR750 3T scanner. Insulin/placebo was delivered using the ViaNase™ electronic atomizers (Kurve Technology, Inc. Lynnwood, WA, USA). Participants administered 40 IU (0.4mL) of human insulin (rDNA origin; Novolin® R, Novo Nordisk Inc., Bagsværd, Denmark) or placebo (0.4 mL bacteriostatic sodium chloride 0.9% solution) intranasally once daily before breakfast. Novolin® R was used off-label14.The MRI protocol included a localizer, 3D T1-weighted BRAVO images, and BOLD rsfMRI images (TR: 2s, 240 image volumes). Participants completed cognitive measure of sustained attention (Rapid Visual Information Processing-A (RVPA, range 0 to 1, worse to better) and balance test with eyes open (EO Total Sway Area).
ALFF maps were derived from BOLD fMRI images. The first six image volumes were discarded to remove the signals before equilibrium. The remaining 234 image volumes were then realigned for head motion correction, corrected for slice timing differences, and spatially normalized to the MNI space. Six rigid-body motion parameters and linear trend were regressed out to reduce effects of head motion and scanner drift. The BOLD data were then filtered with band-pass filter of (0.01- 0.1 Hz). Time series of each voxel were Fourier transformed to frequency domain. The ALFF measure at each voxel was calculated as the averaged square root of the power in the filtered frequency range. The individual ALFF maps were divided by the global mean ALFF value within the brain.
ALFF maps of eight INI-treated subjects between baseline and end-of-treatment were compared using a paired t test. The association between ALFF changes and cognition/balance changes from the baseline to end-of-treatment was evaluated with a general linear regression model. Because of small number of subjects potentially violating normality tests, we adopted nonparametric tests for robust statistical evaluation on a voxel-by-voxel basis using Statistical nonparametric Mapping (SnPM). To further increase the robustness of linear regress analyses, we utilized the rank-based analyses. The voxel-level significance threshold was set for p < 0.005. Five-thousand random permutations were performed to generate the cluster-level statistics. The cutoff cluster size with FWE of 5% was used to correct for multiple comparisons. Post-hoc regional analyses were performed to evaluate the INI vs. placebo effects.

Results & Discussion

ALFF increased significantly from baseline to the end-of-treatment in the superior medial frontal (SMF) region (Fig. 1). Table 1 shows the specific cluster statistics. In this region, INI-treated T2DM subjects had larger ALFF increases compared to those with T2DM-Placebo (p=0.0037, Fig. 2a). ALFF increased in all INI-treated subjects in the SMF region, while decreased in placebo-treated subjects (Fig. 2b). The SMF region with INI-increased ALFF is consistent with INI-induced cerebral blood flow (CBF) increases15. T2DM has been associated with reduced ALFF10 and reduced CBF16 in the SMF region. These results suggest that INI can improve neurovascular activity in the region affected by T2DM.
ALFF increases in the superior/middle temporal (SMT) region and insular region were associated with improved balance (smaller EO Total Sway Area) (Fig. 3a) but decreased levels of sustained attention (lower RVPA values) (Fig. 3b-3c; Table 1), respectively. Regional analyses showed a significant correlation between changes in ALFF and cognition/balance variables after adjusting age and gender (Fig. 4). Positive association of ALFF with balance levels in the SMT region may be associated with a potentially enhanced neuronal signaling from the INI-increased neural activity in the temporal region to the cerebellar balance control system. The insular region in which ALFF was negatively associated with attention levels is consistent with previously reported increased ALFF in the anterior cingulate region (constitutes salience network with insular region)8. The insular association suggests that INI can reduce overactive insular activity that modulates attention levels to salient stimuli17,18.

Conclusion

Intranasal insulin alters brain neurovascular activity in regions related to attention processing and balance control. Intranasal insulin may prove to be an effective intervention to improve functional outcomes in T2DM but larger studies are needed to confirm these results.

Acknowledgements

www.clinicaltrials.gov NCT2415556; NIH-NIDDK 1R01DK103902; ISS-001033 Novo-Nordisk, Inc.; NERP15031 Medtronic Inc.

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Figures

Table 1. Clusters showing significant difference in fluctuation from baseline to follow-up. %Cluster indicates the percentage of each cluster that falls within the defined region, %Region indicates the percentage of each defined region that falls within the cluster. The listed anatomical regions are either “%Cluster” > 2% or “%Region” > 30%.

Figure 1. ALFF significantly increased after intranasal insulin treatment in Superior Medial Frontal Cortex (regions overlaid on a standard brain template). The color bar indicates the range of t values.

Figure 2. (a) Type 2 diabetic subjects on intranasal insulin intervention showed significant ALFF increases in the superior medial frontal region compared to those on placebo. (b) Regional ALFF changes in the superior medial frontal region from the baseline to end treatment for each subject (red – intranasal insulin, blue-placebo).

Figure 3. Regions overlaid on a standard brain template, in which negative association was observed between the longitudinal ALFF changes and (a) Balance measures Total Sway Area during standing with eyes open ) in the right superior temporal region, (b) RVPA in the insular region and (c) RVPA in the superior temporal region. The color bar shows the range of t values.

Figure 4. More increases of ALFF were associated with (a) less increases of EO Total Sway Area in the right superior temporal region and (b) less increases of RVPA in the Insular region. The black line shows the fitting with the T2DM subjects with INI intervention only.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
4958
DOI: https://doi.org/10.58530/2022/4958