Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease

Abstract

Background: Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer's disease; however, both effects and mechanisms require elucidation.

Objective: We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer's disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909).

Design: A randomized (1:1) double-blind clinical trial.

Setting: Twelve sites across the United States.

Participants: Adults with mild cognitive impairment or Alzheimer's disease.

Intervention: Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled.

Measurements: Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer's Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite.

Results: The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer's disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group.

Conclusion: Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin's potential as a therapeutic option for Alzheimer's disease.

Keywords: Alzheimer’s disease; CSF; clinical trial; intranasal insulin; white matter.

Figure 1

CONSORT diagram

Figure 2

Changes in gray matter A) volume and B) surface weighted thickness in the temporal-parietal meta-ROI There were no significant differences between treatment group and placebo. Error bars represent 95% confidence intervals.

Figure 3

White Matter Hyperintensity Volume (WMHV) as percent change from baseline both globally and regionally split by MCALT (excluding cerebellum and midbrain regions) There were significant differences between the degree of change for insulin and placebo groups in the deep white matter and frontal regions with a similar trend for global change (+ p<0.10, * p<0.05). The placebo group showed significantly increased change from baseline WMHV in all regions, whereas the insulin group showed significant change only in temporal lobe with a trend for global change (# <0.10, ## p<0.05). Error bars represent 95% confidence intervals.

Figure 4

Changes in global and regional White Matter Hyperintensity Volume (WMHV) correlate with changes in ADAS-cog, CDR-SB, ADCS-ADL, and a memory composite Analyses were performed for both insulin and placebo groups combined (A) and for the insulin treatment arm (B) and placebo (C) groups independently. Light colors represent correlations with lower p values (ps range from <0.001 to 0.10 from light to dark). Exemplar scatterplots are shown that demonstrate relationships between change in frontal WMHVs (which differed between insulin and placebo groups) and change in (D) CDR-SB, (E) ADCS-ADL, and (F) memory composite scores.

Figure 5

Changes in global and regional White Matter Hyperintensity Volume (WMHV) correlate with changes in CSF AD biomarkers Analyses were performed for both insulin and placebo groups combined (A) and for the insulin treatment arm (B) and placebo (C) groups independently. Light colors represent correlations with lower p values (ps range from <0.001 to 0.10 from light to dark). Exemplar scatterplots are shown that demonstrate relationships between change in frontal WMHVs (which differed between insulin and placebo groups) and change in CSF (D) Aβ42, (E) Aβ42/Aβ40 ratio, and (F) Aβ42/T-tau ratio.